WO2024260368A1 - Benzofuran derivative and preparation method for benzofuran derivative intermediate - Google Patents

Abstract

The present disclosure relates to a benzofuran derivative and a preparation method for a benzofuran derivative intermediate. Specifically, the present disclosure relates to a preparation method for a primary amine compound, comprising the step of reacting a ketone compound with amino sulfonate in the presence of an acid catalyst to directly synthesize a primary amine compound. The method is high in yield, mild in reaction condition and suitable for industrial production.

Description

A method for preparing benzofuran derivatives and intermediates thereof

This application claims the priority of Chinese patent application No. 2023107254915 filed on June 19, 2023. This application cites the entire text of the above Chinese patent application.

Technical Field

The present invention belongs to the field of medicine and relates to a method for preparing a benzofuran derivative and an intermediate thereof.

Background Art

Lymphoma is a malignant tumor originating from the lymphatic hematopoietic system. It is divided into two categories according to the tumor cells: non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). In Asia, 90% of patients suffer from NHL. Pathologically, it is mainly lymphocytes, histiocytes or reticular cells of varying degrees of differentiation. According to the natural course of NHL, it can be classified into three major clinical types, namely highly invasive, invasive and indolent lymphomas; according to the different origins of lymphocytes, it can be divided into B cell, T cell and natural killer (NK) cell lymphomas. The main function of B cells is to secrete various antibodies to help the human body resist various foreign invasions.

The histone methyltransferase encoded by the EZH2 gene is a catalytic component of the polycomb repressive complex 2 (PRC2). Compared with normal tissues, EZH2 levels are abnormally elevated in cancer tissues, and the expression level of EZH2 is highest in advanced cancer or poor prognosis. In some cancer types, excessive EZH2 expression 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.

Currently, there are EZH2 inhibitors that have entered the clinical development stage. The following is a brief list: Tazemetostat (EPZ-6438) developed by Eisai is used to treat non-Hodgkin's B-cell lymphoma and is currently in Phase II clinical trials. CPI-1205 developed by Constellation is used to treat B-cell lymphoma and is currently in Phase I clinical trials. GSK-2816126 developed by GlaxoSmithKline is used to treat diffuse large B-cell lymphoma and follicular lymphoma and is currently in Phase I clinical trials.

PCT application WO2017084494A provides an EZH2 inhibitor, the structure of which is shown in formula (I). WO2019091450A provides a method for preparing the compound shown in formula (I).

In addition, primary aromatic amino groups are present in drugs, dyes, and organic compounds. Synthetic methods for producing primary amines using transition metal catalysts or organometallic reagents have been developed. For example, Bechamp reduction of nitroaromatics using iron catalysts, Pd-catalyzed Buchwald-Hartwig coupling of halogenated aromatics, Chan-Lam amination of boron compounds, Ni-catalyzed decarbonation amination of aromatic esters and amides, and electrophilic amination using organometallic reagents (Grignard reagents, Li, Zn) have been reported. In particular, C-H amination reactions have attracted attention because they do not require the preparation of pre-oxidized starting materials.

However, these methods have disadvantages, such as the use of expensive transition metals and designed ligands, the need to remove trace metal impurities from the products, and the inability to control the reaction site selectivity under non-directing group conditions during C–H amination.

Kengo Hyodo et al. (Org. Lett. 2019, 21, 8, 2818–2822) reported a new method for preparing primary amines, using a new oxime reagent as an amination reagent to participate in the reaction. However, the oxime reagent has a high preparation cost, is an oily substance at room temperature and is not easy to store, and has a low conversion rate for preparing aniline.

Summary of the invention

On the one hand, the present disclosure provides a method for preparing a primary amine compound represented by formula (B-I), comprising the steps of reacting a ketone compound represented by formula (B-II) and a sulfonic acid amino ester in the presence of an acid catalyst,

R is an aryl or C ₁ -C ₁₀ alkyl group optionally substituted by one or more substituents, R' is selected from a C ₁ -C ₆ alkyl group optionally substituted by one or more substituents, and the ketone compound represented by formula (B-II) is, for example, acetophenone, p-methylacetophenone, p-methoxyacetophenone, p-chloroacetophenone, p-nitroacetophenone, 5-ethyl-2-methoxyacetophenone, benzyl acetone, acetylcyclohexane, 2-decanone,

The sulfonic acid amino ester is a compound represented by formula C or a salt thereof, wherein _R1 is selected from _{C1 - C6} alkyl, C1- _C6 alkyl substituted by 1-3 halogen atoms, _C3 - _C6 cycloalkyl and phenyl, and the phenyl is optionally substituted by one or more substituents selected from halogen, cyano, nitro, _C1 - _C6 alkyl, and C1- _C6 alkyl substituted by 1-3 _halogen atoms; _R2 is selected from hydrogen atom, 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

In some embodiments, the aforementioned substituents are independently selected from C ₁ -C ₆ alkyl, halogen, deuterium, hydroxyl, thiol, -NR _i R _j , oxo, thioxo, -C(O)R _k , -C(O)OR _k , -S(O)R _k , -S(O)OR _k , -S(O)(O)R _k , -S(O)(O)OR _k , -C(S)R _k , nitro, cyano, C _{1 -C 6 alkoxy, C 1 -C 6 alkylthioether, C 2 -C 6 alkenyl} , C ₂ -C ₆ alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 8 to 12 membered fused ring aryl and 5 to 12 membered fused heteroaryl, wherein,

R _i and R _j are each independently selected from a hydrogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group; R _k is independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, and a -NR _i R _j , wherein the alkyl group, the alkoxy group, and the haloalkyl group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a halogen group, a hydroxyl group, a thiol group, -NR _i R _j , an oxo group, a thioxo group, a carboxyl group, a nitro group, a cyano group, a C _{1 -C 6 alkoxy group, a C 1 -C 6 alkylthioether} group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group.

In some embodiments, the sulfonic acid amino ester is

In some embodiments, the primary amine compound represented by formula (B-I) is selected from aniline, p-methylaniline, p-methoxyaniline, p-chloroaniline, p-nitroaniline, 5-ethyl-2-methoxyaniline, phenethylamine, cyclohexylamine, and octylamine.

In some embodiments, the molar ratio of the ketone compound to the sulfonic acid amino ester is 1:1-1:3, such as 1:1-1:2 or 1:1.1-1:1.5.

In some embodiments, the acid catalyst is Acid or Lewis acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, bistrifluoromethanesulfonimide, boron trifluoride ether complex, scandium (III) trifluoromethanesulfonate, iron (III) trifluoromethanesulfonate, copper (II) trifluoromethanesulfonate, bismuth (III) trifluoromethanesulfonate, trifluoroacetic acid, phosphorus pentachloride, titanium tetrachloride and ferric chloride. In some embodiments, the acid catalyst is selected from p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphorus pentachloride, ferric chloride.

In some embodiments, the molar ratio of the ketone compound to the acid catalyst is 1:0.05-1:3, for example, 1:0.05-1:0.1 or 1:1-1:3.

In some embodiments, the solvent is one or more of lower alcohol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, n-hexane, toluene. In some embodiments, the solvent is methanol. or ethanol.

In some embodiments, the reaction temperature is between 0-60°C, such as 15-30°C, such as 40-50°C.

The preparation method disclosed in the present invention opens up a new low-cost green approach for the preparation of amine compounds, and has the advantages that the sulfonic acid amino ester reagent used is low in price, the reaction conditions are mild, the operation is safe and simple, there is less pollution, and the yield is high.

Another aspect of the present disclosure provides a method for preparing a compound represented by formula (A-II) or a salt thereof, comprising the step of reacting a compound represented by formula (A-III) with 1-propargylpiperidine in the presence of a metal catalyst to prepare a compound represented by formula (A-II), wherein:

X is a halogen, such as bromine;

R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, for example ethyl;

R ₂ is a carboxyl protecting group, such as a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, such as a methyl group or an ethyl group;

In some embodiments, the metal catalyst is selected from one or more of a metal palladium catalyst, a metal zinc catalyst, a metal copper catalyst, and _a metal nickel catalyst, and non-limiting examples include one or more of _Pd2 (dba) ₃ , Pd(dba) ₂ , Pd( _PPh3 ) ₄ , _PCy3 -Pd-G3, ( _Ph3P ) _2PdCl2 , Pd(OAc) ₂ , Pd(tfa) ₂ , Pd(Piv) ₂ , Pd(OTf) ₂ , Pd/ _C , CuI, CuBr, CuCl, _Cu2O , and ZnCl2. In some embodiments, the molar ratio of the compound represented by formula (A-III) to the metal catalyst is 1:0.001-1:0.2, for example, 1:0.001, 1:0.005, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2 or any value in between.

In some embodiments, the metal catalyst is a combination of (Ph ₃ P) ₂ PdCl ₂ and CuI or a combination of Pd ₂ (dba) ₃ and CuI. The molar ratio of (Ph ₃ P) ₂ PdCl ₂ or Pd ₂ (dba) ₃ and CuI is 1:0.1-1:10, such as 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or any value in between.

In some embodiments, the reaction is carried out in the presence of a phosphine ligand, and the phosphine ligand is selected from one of a monophosphine ligand and a diphosphine ligand, such as PCy ₃ , PCy ₃ .HBF ₄ , XantPhos, BINAP, dppf, Bu(Ad) ₂ P, PPh ₃ , Xphos, DavePhos, and CyJohnPhos, such as PCy ₃ , wherein the molar ratio of the compound represented by formula (A-III) to the phosphine ligand is 1:0.01-1:0.5, such as 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2, 1:0.3, 1:0.4 or any value in between any two numbers.

In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from one or more of an inorganic base and an organic base, such as one or more of Cs ₂ CO ₃ , K ₃ PO ₄ , K ₂ CO ₃ , potassium acetate, potassium benzoate, DBU, prolinol, piperidine, triethylamine, diisopropylamine, pyridine, DIPEA, TMEDA, and TMPDA, such as a combination of Cs ₂ CO ₃ and K ₃ PO ₄ , and the molar ratio of the compound represented by formula (A-III) to the base is 1:1-1:5, such as 1:1, 1:2, 1:3, 1:4, or any value between the two numbers. In some embodiments, the base is a combination of Cs ₂ CO ₃ and K ₃ PO _4. The molar ratio of Cs ₂ CO ₃ and K ₃ PO ₄ is 1:1-1:3, such as 1:1, 1:2, 1:3, or any value between the two numbers.

In some embodiments, the reaction temperature is 0-100°C, such as 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C or any value in between.

In some embodiments, the method further comprises the step of reacting the compound represented by formula (A-IV) to prepare the compound represented by formula (A-III), wherein R ₃ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, such as methyl,

In some embodiments, the reaction is carried out in the presence of a nucleophile and a Lewis acid, and the nucleophile is preferably tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylmercaptopropionate, ethyl 2-methylmercaptoacetate, 3-methylmercaptopropanol, preferably tetrabutylammonium iodide; the Lewis acid is preferably boron chloride, boron bromide, boron iodide, dimethylboron bromide, aluminum chloride, aluminum bromide, preferably boron chloride.

In some embodiments, the reaction temperature is -20-30°C, such as -10-10°C, 10-25°C.

In some embodiments, the method further comprises the step of reacting the compound represented by formula (AV) to prepare the compound represented by formula (A-IV),

In some embodiments, the reaction is carried out in the presence of an acid, a diazotizing agent, and an iodinating agent. The acid is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride ether complex, trifluoroacetic acid; the diazotizing agent is preferably NaNO2, KNO2, isoamyl nitrite, tert-butyl nitrite; the iodination agent is preferably KI, NaI, TBAI, NIS, I( _Py ) _2BF4 , IOAC, _KIO3 and IBr.

In some embodiments, the reaction temperature is -10-30°C.

In some embodiments, the method further comprises the step of reacting the compound represented by formula (A-IV-1) to prepare the compound represented by formula (A-III),

In some embodiments, the reaction is carried out in the presence of an acid, a diazotizing agent and an iodizing agent. The acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride ether complex, trifluoroacetic acid, the diazotizing agent is selected from NaNO2, KNO2, _isopentyl nitrite, tert-butyl nitrite, and the iodizing agent is selected from KI, NaI, TBAI, NIS, I(Py) _2BF4 , IOAC, _KIO3 and IBr.

In some embodiments, the reaction temperature is -10-50°C.

In some embodiments, the method further comprises the step of reacting the compound represented by formula (AV) to prepare the compound represented by formula (A-IV-1), wherein _R3 is selected from _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy and _C1 - _C6 haloalkoxy, such as methyl,

In some embodiments, the reaction is carried out in the presence of a nucleophile and a Lewis acid, the nucleophile is selected from tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylmercaptopropionate, ethyl 2-methylmercaptoacetate, 3-methylmercaptopropanol, for example ethyl 3-methylmercaptopropionate; the Lewis acid is selected from boron chloride, boron bromide, boron iodide, dimethylboron bromide, aluminum chloride, aluminum bromide, methanesulfonic acid, preferably aluminum chloride.

In some embodiments, the reaction temperature is -20-35°C, eg, -10-10°C, 10-35°C.

In some embodiments, the method further comprises the step of reacting the compound represented by formula (A-VI) to prepare the compound represented by formula (AV),

In some embodiments, X is bromine, and the reaction is carried out in the presence of a brominating agent selected from HBr, Br ₂ , NBS, DBDMH, HOBr, AcOBr, CF ₃ COOBr, NH ₄ Br, TBBDA, PBBS, tribromoisocyanourea, such as NBS, DBDMH.

In some embodiments, the reaction temperature is -10-30°C.

On the other hand, the present disclosure provides a method for preparing a compound represented by formula (AI) or a salt thereof, the method comprising the step of preparing a compound represented by formula (A-II) as described in the present disclosure, and the step of deprotecting the compound represented by formula (A-II) to prepare a compound represented by formula (AI) or a salt thereof,

In some embodiments, the salt of the compound represented by formula (A-I) can be an inorganic acid salt and an organic acid salt. The inorganic acid salt can be a hydrochloride, a sulfate, a phosphate, a hydrobromide, a trifluoroacetate, etc., and the organic acid can be a format, an acetate, a sulfonate, an arbitrarily substituted alkyl sulfonate, a succinate, a maleate, a tartrate, a citrate, a lactate, an oxalate, a gluconate, a fumarate, a malonate, a malate, etc.

On the other hand, the present disclosure provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of preparing a compound represented by formula (A-I) or a salt thereof as described in the present disclosure.

In some embodiments, the method further comprises the following steps,

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be prepared by referring to the methods disclosed in WO2019091450A and WO2023061467A, which are cited herein in their entirety.

In some embodiments, each reaction solvent described in the present disclosure is independently selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol, and water.

In some embodiments, the preparation method of the present disclosure optionally further comprises a purification step, wherein the purification step comprises one or more of column chromatography, solvent slurrying and recrystallization.

Another aspect of the present disclosure provides a compound represented by formula (A-II), wherein:

X is a halogen, such as bromine;

R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, for example ethyl;

_R2 is a carboxyl protecting group, such as a _C1 - _C6 alkyl group, a _C6 - _C10 aryl group, such as a methyl group or an ethyl group,

Another aspect of the present disclosure provides a compound represented by formula (A-III), wherein R ₁ , R ₂ , and X are as defined above,

Another aspect of the present disclosure provides a compound represented by formula (A-IV), wherein R ₁ , R ₂ , and X are as defined above, and R ₃ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkoxy, such as methyl,

Another aspect of the present disclosure provides a compound represented by formula (A-IV-1), wherein R ₁ , R ₂ , and X are as defined above,

Another aspect of the present disclosure provides a compound represented by formula (AV), wherein R ₁ , R ₂ , R ₃ , and X are as defined above,

Another aspect of the present disclosure provides compound A-05,

The preparation method of the benzofuran derivative disclosed in the present invention has high reaction yield, mild reaction conditions, lower route cost, and is more suitable for industrial production.

In the preparation method disclosed in the present invention, the reactions connected by “→” all refer to a one-step reaction to obtain the product.

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, and more preferably an alkyl group containing 1 to 6 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, 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-dimethylpentyl, 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-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

"Carboxyl protecting group" is a suitable group for carboxyl protection known in the art, see the carboxyl protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GMWuts), as an example, preferably, the carboxyl protecting group can be a substituted or unsubstituted C _1-10 straight or branched alkyl group, a substituted or unsubstituted C _2-10 straight or branched alkenyl or alkynyl group, a substituted or unsubstituted C _3-8 cyclic alkyl group, a substituted or unsubstituted C _5-10 aryl or heteroaryl group, or a (C _1-8 alkyl or aryl) ₃ silyl group; preferably a C _1-6 straight or branched alkyl group, more preferably a C _1-4 straight or branched alkyl group. For example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

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

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations.

Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

DETAILED DESCRIPTION

The present disclosure will be explained in detail below in conjunction with specific examples so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

Reagents and Abbreviations:

P/E: Petroleum ether/ethyl acetate

Example 1 Synthesis of 4-methylbenzenesulfonic acid (tert-butyloxycarbonylamino) ester (Formula C1)

Tert-butyl N-hydroxycarbamate (100.0g, 0.75mol, 1.0eq) is dissolved in methyl tert-butyl ether (500mL), 4-methylbenzenesulfonyl chloride (143.2g, 0.75mol, 1.0eq) is added, transferred to an ice bath, the temperature in the system is reduced to 5-10°C, triethylamine (79.8g, 0.79mol, 1.05eq) is added dropwise, DMAP (4.6g, 37.5mmol, 0.05eq) is added thereto and stirred in an ice bath for 0.5h, then gradually warmed to room temperature and stirred for 4-5h. The reaction is monitored by TLC to complete, filtered, washed, and the organic phase is concentrated under reduced pressure. The crude product is pulped with petroleum ether (500mL), filtered, and the filter cake is dried at room temperature to obtain a total of 201.0g of solid compound C1, with a yield of 88%.

Example 2 Synthesis of Compound A-03 (Using Compound C1)

Compound A-02 (93.0 g, 0.52 mol, 1.0 eq), compound C1 (180.0 g, 0.63 mol, 1.2 eq) and methanol (500 mL) were added to the reaction flask and stirred to dissolve; at room temperature, a solution of TsOH·H ₂ O (298.0 g, 1.57 mol, 3.0 eq) in methanol (500 mL) was added to the stirred reaction mixture; the reaction was carried out at room temperature for 16 h, and the reaction of the raw materials was complete as determined by TLC; most of the methanol was removed by rotary evaporation, and then 1 L of tert-methyl ether and an ice-water solution of NaOH (100 g NaOH, 1.5 L ice water) were added to the system, stirred to separate the liquids, and the aqueous phase was extracted once with tert-methyl ether (1 L), and the organic phases were combined; the organic phase was washed once with 500 mL of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 80.3 g of compound A-03 with a yield of 85%.

Example 3 Synthesis of Compound B (Using Compound C1)

Benzyl acetone (10.0 g, 67.5 mmol, 1.0 eq), compound C1 (23.3 g, 81.0 mmol, 1.2 eq) and methanol (60 mL) were added to the reaction flask and stirred to dissolve. TsOH·H ₂ O (38.5 g, 202.4 mmol, 3.0 eq) of methanol (60 mL) was added to the stirred reaction mixture; the reaction was carried out at room temperature for 16 h. The reaction of the raw material was complete as determined by TLC; most of the methanol was removed by rotary evaporation, and then 100 mL of tert-methyl ether and an ice-water solution of NaOH (10 g NaOH, 150 mL ice water) were added to the system. The mixture was stirred and separated, and the aqueous phase was extracted once with tert-methyl ether (100 mL), and the organic phases were combined; the organic phase was washed once with 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 6.7 g of compound B with a yield of 82%.

Example 4 Synthesis of Compound A-03 (using Compound D, a reagent used in Org. Lett. 2019, 21, 8, 2818-2822)

Compound A-02 (10.0 g, 56.1 mmol, 1.0 eq), compound D (27.3 g, 112.2 mmol, 2 eq) and methanol (100 mL) were added to the reaction flask and stirred to dissolve; TsOH·H ₂ O (1.1 g, 5.6 mmol, 0.1 eq) was added to the stirred reaction mixture at room temperature; the reaction was carried out at room temperature for 16 h, and a small amount of raw material was still left after TLC detection; most of the methanol was removed by rotary evaporation, and then 100 mL of tert-methyl ether and NaOH ice water solution (5.6 g NaOH, 100 mL ice water) were added to the system, stirred to separate the liquids, and the aqueous phase was extracted once with tert-methyl ether (100 mL), and the organic phases were combined; the organic phase was washed once with 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 4.4 g of compound A-03 with a yield of 52%.

Example 5 Synthesis of Compound A

Step 1: Synthesis of Compound A-01

Add p-ethylphenol (200 g, 1.64 mol) and DMAc (1.6 L) to the reaction flask, stir and dissolve until clear; then add powdered K ₂ CO ₃ (452 g, 3.28 mol) and trimethyl phosphate (459 g, 3.28 mol), stir and mix thoroughly; raise the temperature of the reaction system to 100°C, and react for 16-18 h; after TLC detection (P/E=10:1) shows that the reaction is complete, stop heating and reduce the reaction temperature to below 50°C; add 3.2 L of water and 2.0 L of petroleum ether to the reaction system, stir and mix for 0.5 h, and then stand to separate the liquids; the aqueous phase is extracted once with 1.0 L of petroleum ether, the organic phases are combined, washed with 1.0 L of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 214 g of the title compound in a yield of 95%.

Step 2: Synthesis of Compound A-02

1.5L of dichloromethane was added to the reaction flask, and AlCl ₃ (249g, 1.87mol) was added while stirring. Then the system was placed at -10°C, and A-01 (121g, 0.89mol) was slowly added. Then the system was replaced with nitrogen three times. A dichloromethane solution (300mL) of acetic anhydride (95g, 0.93mol) was slowly dripped into the system and stirred for 10-20min. After TLC detection (P/E=10:1) showed that the reaction was complete, the system was slowly poured into a 1M HCl ice water solution (1.8L) and stirred for 0.5h. The mixture was allowed to stand and separated, and the aqueous phase was extracted once with 300mL of dichloromethane. The organic phases were combined, washed once with 500mL of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 154g of the title compound with a yield of 96%.

Step 3: Synthesis of Compound A-03

According to the method of Example 2, A-02 (93 g, 0.52 mol) was added to obtain 80.3 g of the title compound with a purity of 83% and a yield of 84%.

Step 4: Synthesis of Compound A-04

Add 1.2L of water, sodium sulfate (260g, 1.83mol), and chloral hydrate (78.4g, 0.48mol) to the reaction flask. Heat to 50°C and dissolve until clear; A-03 (55.2 g, 0.37 mol) is stirred and dissolved in 2M dilute sulfuric acid (0.37 mol); the dissolved A-03 solution is added to the system, and then 650 mL of ethanol is added thereto, and the system begins to heat to 85°C, and an aqueous solution (180 mL) of hydroxylamine sulfate (90 g, 0.55 mol) is added, and the reaction is performed for 4-5 hours; after TLC detection (P/E=4:1) shows that the reaction is complete, heating is stopped, and after cooling to 60°C, 1.5 L of water is added thereto; after cooling to room temperature, stirring is continued for 0.5 h, filtered, and washed with 1 L of water, and the filter cake is dried at 50°C; 60 g of the dried product is obtained, 300 mL of dichloromethane is added thereto, pulping is performed at room temperature for 2-3 hours, and 61 g of the intermediate is obtained by filtration, with a yield of 75%.

Add 250 mL of methanesulfonic acid to the reaction flask, and slowly add 50 g of the intermediate obtained above while stirring at room temperature; stir at 60 ° C for 0.5 h, and the reaction is complete after TLC detection (P/E=2:1); stop heating, cool to room temperature, slowly pour into 2 L of ice water while stirring, and stir for 0.5 h; precipitate solid, filter, and dry at 50 ° C to obtain 44 g of the title compound with a yield of 95%.

Step 5: Synthesis of Compound A-05

A-04 (38.5 g, 0.19 mol), 580 mL of methanol, and 70% tert-butyl hydroperoxide (49 g, 0.38 mol) were added to the reaction bottle and stirred to mix evenly; the reaction system was placed in an ice bath, and K ₂ CO ₃ (52 g, 0.38 mol) was slowly added while stirring; after stirring for 0.5 h in the ice bath, the mixture was transferred to room temperature and stirred for 3-4 h; TLC detection (P/E=3:1) showed that the reaction was complete, and 10% NaHSO ₃ solution (60 g, 0.57 mol) and 700 mL of petroleum ether were added to the reaction system while stirring; the mixture was fully stirred, and 500 mL of water was added; the mixture was separated, and the aqueous phase was extracted once with 350 ml of petroleum ether, the mixture was separated, the organic phases were combined, the organic phases were washed once with 300 mL of brine, and dried over anhydrous sodium sulfate; the mixture was filtered, and the solvent was removed by concentration to obtain 31.5 g of the title compound with a yield of 85% and a HPLC purity of 98%.

LC-MS: [M+H] ⁺ = 210.11

¹ H NMR (400MHz, DMSO): δ6.74 (d, 1H, J = 8.4Hz), 6.50 (d, 1H, J = 8.4Hz), 4.96 (s, 2H), 3.90 (s, 3H), 3.83 (s ,3H),2.73(q,2H,J＝7.5Hz),1.15(t,3H,J＝7.6Hz).

Step 6: Synthesis of Compound A-06

A-05 (28.7 g, 137.3 mmol) and 400 mL of acetone were added to the reaction flask, stirred and mixed evenly, and placed in a -10--15°C cold trap, and NBS (25.7 g, 144.2 mmol) was added, and the reaction was carried out at 0°C for 1-1.5 h. The reaction was complete as detected by TLC (P/E=6:1); 150 mL of 10% NaHSO ₃ solution (15 g, 137.3 mmol) was added to the reaction system, and stirred for 10-20 min. Then 650 mL of water and 400 mL of petroleum ether were added, and stirred for 0.5 h; the liquids were separated, and the aqueous phase was extracted once with 300 mL of petroleum ether, the liquids were separated, the organic phases were combined, and the mixture was washed once with 200 mL of brine, and dried over anhydrous sodium sulfate; the organic solvent was removed by rotary evaporation to obtain 35.4 g of the title compound, with a yield of 90% and a HPLC purity of 96%.

LC-MS: [M+H] ⁺ = 288.02

¹ H NMR (400MHz, DMSO): δ7.05 (s, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.59 (q, 2H, J = 7.3Hz) ,1.07(t,3H,J=7.2Hz).

Step 7: Synthesis of Compound A-07

Add A-06 (26.4 g, 91.6 mmol) and 225 mL of acetone to the reaction bottle and stir evenly; add 184 mL of 3 M concentrated hydrochloric acid (549.4 mmol) to the system, stir evenly, place the system in ice water, and stir for 10-15 min; Slowly add 46mL NaNO2 _aqueous solution (12.6g, 183.1mmol) dropwise thereto, and stir for 0.5h; then add 46mL KI aqueous solution (31.9g, 192.3mmol) dropwise thereto, and continue stirring in ice water for 0.5-1h, transfer the system to room temperature, and stir for 16-18h; after TLC detection (P/E=8:1) the reaction is complete, pour in 200mL 10% _NaHSO3 solution (20g, 192.3mmol), stir for 10-20min, then add 200mL water and 400mL tert-methyl ether, and stir for 10-20min; separate the liquids, extract the aqueous phase once with 300mL tert-methyl ether, separate the liquids, combine the organic phases, wash once with 200mL brine, and dry over anhydrous sodium sulfate; concentrate, purify by column chromatography (P/E=2.5%-5%), and obtain 35.2g of the title compound, with a yield of 96% and a HPLC purity of 98%.

MS: m/z = 397.90

¹ H NMR (400MHz, DMSO): δ7.30 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.58 (q, 2H, J = 7.6Hz), 1.07 (t, 3H, J=7.4Hz).

Step 8: Synthesis of Compound A-08

A-07 (8.6 g, 21.6 mmol), 55 mL of dichloromethane, and tetrabutylammonium iodide (9.6 g, 25.9 mmol) were added to a three-necked flask, and the mixture was stirred and dissolved until clear; the system was replaced with nitrogen, and then the system was placed in a -10°C to -20°C cold trap, and 1 M boron trichloride dichloromethane solution (6.31 g, 53.9 mmol) was slowly added dropwise thereto, and then reacted at 0°C for 16-18 h; TLC detection (P/E=5:1) showed that the reaction was complete, and the internal temperature of the system was lowered to about -10°C, and 20 mL of methanol was added thereto to quench, and then the system was transferred to room temperature and stirred for 0.5 h; 200 mL of dichloromethane and 100 mL of 10% NaHSO were added to the system. ₃ aqueous solution, separate the liquids, and extract the aqueous phase with 150 mL of dichloromethane; combine the organic phases, wash once with 200 mL of aqueous ammonium chloride solution, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (P/E=5%-10%); obtain 8.2 g of the title compound with a yield of 99% and a HPLC purity of 99%.

LC-MS: [MH] ^- = 382.89

¹ H NMR (400MHz, DMSO): δ10.94 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 2.53 (q, 2H, J = 7.5Hz), 1.05 (t, 3H, J＝7.6Hz).

Step 9: Synthesis of Compound A-09

A-08 (5.8 g, 15.0 mmol), 75 mL of isopropyl acetate, triphenylphosphine (158 mg, 0.6 mmol), bis(triphenylphosphine)palladium(II) chloride (211 mg, 0.3 mmol), cuprous iodide (115 mg, 0.6 mmol), 1-propargylpiperidine (2.8 g, 22.6 mmol) were added to a single-mouth bottle and stirred to mix evenly; the system was replaced with nitrogen three times, and then diisopropylamine (4.6 g, 45.1 mmol) was added to the system; the reaction mixture was heated to 65 ° C, reacted for 16 h, and the reaction was complete by TLC detection (P/E=4:1); the system was cooled to 25 ° C, the solid in the system was removed by diatomaceous earth filtration, and washed with 20 mL of isopropyl acetate; the organic phase was washed with 5% NaHCO ₃ aqueous solution (100 mL × 2) and 100 mL of distilled water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (P/E = 5%-15%) to obtain 3.7 g of the title compound with a yield of 65% and a HPLC purity of 98%.

LC-MS: [M+H] ⁺ = 380.08

¹ H NMR (400MHz, DMSO): δ8.10(s,1H),6.81(s,1H),3.87(s,3H),3.63(s,2H),2.96 (q,2H,J＝7.3Hz),2.41(s,4H),1.49(s,4H),1.36(s,2H),1.15(t,3H,J＝7.5Hz).

Step 10: Synthesis of Compound A

Add A-09 (2.5 g, 6.6 mmol) and 20 mL of ethanol to the reaction bottle, stir and dissolve until clear; add 10 mL of NaOH (0.8 g, 19.8 mmol) solution to the system, heat to 65°C, and react for 6-8 h; TLC detection (P/E=1:1), the reaction is complete, stop heating; remove ethanol, add 13 mL of 6 M HCl to the system, stir at 40°C for 1.5 h, filter, and rinse with purified water; add 5 V acetone to the residue, slurry for 0.5 h, filter, and dry to obtain 2.3 g of the title compound with a yield of 95% and a HPLC purity of 98%.

LC-MS: [MH] ^- = 364.06

¹ H NMR (400MHz, DMSO): δ8.01(s,1H),7.35(s,1H),4.56(s,2H),3.55(d,2H,J＝12Hz),3.16(q,2H,J＝7.2 Hz), 3.07(t,2H,J＝12.6Hz),1.97(d,2H,J＝14Hz),1.85-1.73(m,3H),1.57-1.50(m,1H),1.25(t,3H,J＝3.8 Hz).

Example 6

Step 1: Synthesis of Compound A-07-1

Add 260mL of dichloromethane and AlCl3 (83.3g, 624mmol) to the reaction flask, cool to 10℃, add A-06 (30g, 104mmol) in dichloromethane (130mL) dropwise to the reaction system, stir, add 3-methylthiopropionic acid ethyl ester (18.5g, 125mmol) in dichloromethane (60ml) dropwise to the reaction system, then transfer to a 37℃ oil bath, stir and react overnight. After the reaction is complete, slowly pour the reaction system into 1.2L 20% sodium citrate (242g, 936mmol) ice water solution, stir, adjust the pH of the system to about 6-7 with NaOH, add 400mL of dichloromethane and stir, separate the liquids, wash the organic phase once with water, dry over anhydrous Na2SO4, filter, and rotary evaporate to obtain a crude product, slurry with petroleum ether, filter, and obtain 20.6g of the title product with a yield of 71% and a purity of 98%.

LC-MS: [M+H] ⁺ = 274.11

¹ H NMR (400MHz, DMSO): δ9.89 (s, 1H), 6.90 (s, 1H), 4.95 (s, 2H), 3.83 (s, 3H), 2.51 (q, 2H, J = 7.6Hz) ,1.05(t,3H,J=7.4Hz).

Step 2: Synthesis of Compound A-08

Add A-07-1 (26.4 g, 91.6 mmol) and 265 mL of acetone to the reaction bottle and stir evenly; add 130 mL of dilute sulfuric acid (274.8 mmol) to the system and stir evenly. Place the system in ice water and stir. Slowly add 65 mL of NaNO ₂ aqueous solution (6.3 g, 91.6 mmol) was added dropwise, and then 65 mL of KI aqueous solution (24.3 g, 146.6 mmol) was added dropwise thereto, and stirring was continued in ice water for 0.5-1 h. The system was transferred to 50 ° C. and stirred overnight. After the reaction was complete, 200 mL of 10% NaHSO ₃ solution (20 g, 192.3 mmol) was poured into it, and then 200 mL of water and 400 mL of tert-methyl ether were added, and the liquid was separated. The aqueous phase was extracted once with 300 mL of tert-methyl ether, and the organic phases were combined, washed once with 200 mL of brine, and dried over anhydrous sodium sulfate; concentrated, and purified by column chromatography (P/E=2.5%-5%) to obtain 35.2 g of the title compound with a yield of 96% and a HPLC purity of 98%.

Step 3: Synthesis of Compound A-09

A-08 (10 g, 26 mmol) and 95 ml toluene/acetonitrile = 5:1 were added to a 250 ml reactor in sequence, and stirred to dissolve. Cs2CO3 (4.2 g, 13 mmol), K3PO4 (8.3 g, 39 mmol), 1-propargylpiperidine (3.4 g, 27.3 mmol), CuI (89 mg, 0.47 mmol), Pd2(dba)3 (71.4 mg, 0.078 mmol) were then added in sequence, stirred evenly, and sealed; nitrogen was bubbling and replaced for 30-40 min, and then dissolved in 5 ml toluene/acetonitrile = 5:1 PCy3 (218 mg , 0.78mmol) (nitrogen protection) was added to the reaction system through a syringe, and the reaction was carried out at 100°C overnight. TLC monitoring (P/E=4:1) showed that the basic reaction was completed. The reaction solution was filtered through diatomaceous earth and rinsed with 200ml of ethyl acetate; 300ml of water was added to the filtrate, washed, separated, and the aqueous phase was extracted twice with 150ml of ethyl acetate; the organic phases were combined, washed once with 300ml of brine, separated, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 11g of a crude product; purified by column chromatography (P/E=5%-15%) to obtain 8.4g of the title compound with a yield of 85% and an HPLC purity of 98%.

Since the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalent changes will be apparent to one skilled in the art and are intended to be included within the scope of the disclosure.

Claims (20)

A method for preparing a primary amine compound represented by formula (B-I), comprising the steps of reacting a ketone compound represented by formula (B-II) and a sulfonic acid amino ester in the presence of an acid catalyst, wherein R is selected from an aryl group or a C ₁ -C ₁₀ alkyl group optionally substituted by one or more substituents, R' is selected from a C ₁ -C ₆ alkyl group optionally substituted by one or more substituents, preferably the ketone compound represented by formula (B-II) is selected from acetophenone, p-methylacetophenone, p-methoxyacetophenone, p-chloroacetophenone, p-nitroacetophenone, 5-ethyl-2-methoxyacetophenone, benzyl acetone, acetylcyclohexane and 2-decanone, and the primary amine compound represented by formula (BI) is selected from aniline, p-methylaniline, p-methoxyaniline, p-chloroaniline, p-nitroaniline, 5-ethyl-2-methoxyaniline, phenethylamine, cyclohexylamine and octylamine, The sulfonic acid amino ester is a compound represented by formula C or a salt thereof, wherein _R1 is selected from _{C1 - C6} alkyl, C1- _C6 alkyl substituted by 1-3 halogen atoms, _C3 - _C6 cycloalkyl and phenyl, and the phenyl is optionally substituted by one or more substituents selected from halogen, cyano, nitro, _C1 - _C6 alkyl, and C1 _{- C6} alkyl substituted by 1-3 halogen atoms; _R2 is selected from hydrogen atom, 2-trimethyl-silylethoxycarbonyl, 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and benzyloxycarbonyl,
The preparation method according to claim 1, wherein the sulfonic acid amino ester is Preferably, the molar ratio of the ketone compound to the sulfonic acid amino ester is 1:1-1:3, more preferably 1:1-1:2, and most preferably 1:1.1-1:1.5. The preparation method according to claim 1 or 2, wherein the acid catalyst is Acid or Lewis acid, preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, bistrifluoromethanesulfonimide, boron trifluoride ether complex, scandium (III) trifluoromethanesulfonate, iron (III) trifluoromethanesulfonate, copper (II) trifluoromethanesulfonate, bismuth (III) trifluoromethanesulfonate, trifluoroacetic acid, phosphorus pentachloride, titanium tetrachloride and ferric chloride, more preferably p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphorus pentachloride, ferric chloride, preferably the molar ratio of the ketone compound to the acid catalyst is 1:0.05-1:3. The preparation method according to any one of claims 1 to 3, wherein the reaction solvent of the reaction is one or more of lower alcohols, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, n-hexane, and toluene, preferably methanol or ethanol. A method for preparing a compound represented by formula (A-II) or a salt thereof, comprising the step of reacting a compound represented by formula (A-III) with 1-propargylpiperidine in the presence of a metal catalyst to prepare a compound represented by formula (A-II), wherein: X is halogen, preferably bromine; R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, preferably ethyl; _R2 is a carboxyl protecting group, preferably a _C1 - _C6 alkyl group, a _C6 - _C10 aryl group, more preferably a methyl group or an ethyl group,
The preparation method according to claim 5, wherein the metal catalyst is selected from one or more of a metal palladium catalyst, a metal zinc catalyst, a metal copper catalyst, and a metal nickel catalyst, preferably one or more of _Pd2 (dba) ₃ , Pd(dba) ₂ , _PCy3 -Pd-G3, Pd( _PPh3 ) ₄ , ( _Ph3P ) _2PdCl2 , Pd(OAc) ₂ , Pd(tfa) ₂ , Pd(Piv) ₂ , Pd( _OTf ) ₂ , Pd/C, CuI, CuBr, CuCl, _Cu2O , and _ZnCl2 , and preferably the molar ratio of the compound represented by formula (A-III) to the metal catalyst is 1:0.001-1:0.2. The preparation method according to claim 5, wherein the metal catalyst is a combination of (Ph ₃ P) ₂ PdCl ₂ and CuI or a combination of Pd ₂ (dba) ₃ and CuI, and preferably the molar ratio of (Ph ₃ P) ₂ PdCl ₂ or Pd ₂ (dba) ₃ and CuI is 1:0.1-1:10. The preparation method according to any one of claims 5 to 7, wherein the reaction is carried out in the presence of a phosphine ligand, the phosphine ligand is preferably one of a monophosphine ligand and a diphosphine ligand, more preferably one of PCy ₃ , PCy ₃ .HBF ₄ , XantPhos, BINAP, dppf, Bu(Ad) ₂ P, PPh ₃ , Xphos, DavePhos, and CyJohnPhos, most preferably PCy ₃ , and the molar ratio of the compound represented by formula (A-III) to the phosphine ligand is preferably 1:0.01-1:0.5. The preparation method according to any one of claims 5 to 8, wherein the reaction is carried out in the presence of a base, and the base is preferably one or more of an inorganic base and an organic base, more preferably Cs ₂ CO ₃ , K ₃ PO ₄ , K ₂ CO ₃ , potassium acetate, potassium benzoate, DBU, prolinol, piperidine, triethylamine, diisopropylamine, pyridine, DIPEA, TMEDA, TMPDA One or more of the above, most preferably a combination of Cs ₂ CO ₃ and K ₃ PO ₄ , preferably the molar ratio of the compound represented by formula (A-III) to the base is 1:1-1:5. The preparation method according to any one of claims 5 to 9, wherein the method further comprises the step of reacting the compound represented by formula (A-IV) to prepare the compound represented by formula (A-III), wherein R ₃ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, preferably methyl,
The preparation method according to claim 10, wherein the reaction is carried out in the presence of a nucleophile and a Lewis acid, the nucleophile is preferably tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylthiopropionate, ethyl 2-methylthioacetate, 3-methylthiopropanol, more preferably tetrabutylammonium iodide; the Lewis acid is preferably boron chloride, boron bromide, boron iodide, dimethyl boron bromide, aluminum chloride, aluminum bromide, more preferably boron chloride. The preparation method according to any one of claims 10-11, wherein the method further comprises the step of preparing the compound represented by formula (A-IV) by reacting the compound represented by formula (AV) in the presence of an acid, a diazotizing agent and an iodizing agent, wherein the acid is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride ether complex, trifluoroacetic acid, the diazotizing agent is preferably NaNO2, KNO2, isoamyl nitrite, tert-butyl nitrite, and the iodizing agent is preferably KI, NaI, TBAI, NIS, I(Py) _{2BF4 ,} IOAC, _KIO3 and IBr,
The preparation method according to any one of claims 5 to 9, wherein the method further comprises the step of preparing the compound represented by formula (A-III) by reacting the compound represented by formula (A-IV-1) in the presence of an acid, a diazotizing agent and an iodizing agent, wherein the acid is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride ether complex, trifluoroacetic acid, the diazotizing agent is preferably NaNO2, KNO2, isoamyl nitrite, tert-butyl nitrite, the iodizing agent is preferably KI, NaI, TBAI, NIS, I(Py) ₂ BF ₄ , IOAC, KIO ₃ and Ibr,
The preparation method according to claim 13, further comprising the step of reacting the compound represented by formula (AV) to prepare the compound represented by formula (A-IV-1), wherein R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably methyl,
The preparation method according to claim 14, wherein the reaction is carried out in the presence of a nucleophile and a Lewis acid, wherein the nucleophile is preferably tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylthiopropionate, ethyl 2-methylthioacetate, 3-methylthiopropanol, more preferably ethyl 3-methylthiopropionate; the Lewis acid is preferably boron chloride, boron bromide, boron iodide, dimethyl boron bromide, aluminum chloride, aluminum bromide, methanesulfonic acid, more preferably aluminum chloride. The preparation method according to claim 12 or 14, further comprising the step of reacting the compound represented by formula (A-VI) to prepare the compound represented by formula (AV),
The preparation method according to claim 16, wherein X is bromine, and the reaction is carried out in the presence of a brominating agent, preferably the brominating agent is selected from HBr, _Br2 , NBS, DBDMH, HOBr, AcOBr, _CF3COOBr , _NH4Br , TBBDA, PBBS, tribromoisocyanurate, more preferably NBS, DBDMH. A method for preparing a compound represented by formula (AI) or a salt thereof, the method comprising the step of preparing a compound represented by formula (A-II) according to any one of claims 5 to 17, and the step of preparing a compound represented by formula (AI) or a salt thereof by deprotecting the compound represented by formula (A-II).
A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of preparing a compound represented by formula (AI) or a salt thereof according to claim 18,
A compound which is: The compound represented by formula (A-II),
The compound represented by formula (A-III),
The compound represented by formula (A-IV),

The compound represented by formula (AV),
Compound A-05,
Wherein, X is halogen, preferably bromine; R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, preferably ethyl; _R2 is a carboxyl protecting group, preferably a _C1 - _C6 alkyl group, a _C6 - _C10 aryl group, preferably a methyl group or an ethyl group, R ₃ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy, preferably methyl.