Preparation method of benzofuran derivative and intermediate thereof

Abstract

The invention relates to a preparation method of a benzofuran derivative and an intermediate thereof. Specifically, the invention relates to a preparation method of a primary amine compound, which comprises a step of directly synthesizing the primary amine compound by reacting a ketone compound and a sulfonic acid amino ester in the presence of an acid catalyst. The method is high in yield, mild in reaction condition and suitable for industrial production.

Description

A preparation method of benzofuran derivatives and intermediates thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2023107254915, filed on June 19, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] 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

[0003] Lymphoma is a malignant tumor originating from the lymphopoietic system. It is categorized into non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) based on the tumor cells. In Asia, 90% of patients suffer from NHL. Pathologically, the disease primarily involves lymphocytes, histiocytes, or reticular cells of varying degrees of differentiation. Based on the natural course of NHL, it can be classified into three clinical types: highly aggressive, aggressive, and indolent lymphomas. Based on the different lymphocyte origins, NHL can be divided into B-cell, T-cell, and natural killer (NK) cell lymphomas. The primary function of B cells is to secrete various antibodies to help defend the body against various foreign invasions.

[0004] The EZH2 gene encodes a histone methyltransferase that is a catalytic component of the polycomb repressive complex 2 (PRC2). Compared to normal tissues, EZH2 levels are abnormally elevated in cancer tissues, with highest expression levels observed in advanced cancers or those with poor prognosis. In some cancer types, excessive EZH2 expression is associated with EZH2 gene amplification. Numerous si / shRNA studies have shown that knocking down EZH2 expression in tumor cell lines can inhibit tumor cell proliferation, migration and invasion, angiogenesis, and induce apoptosis.

[0005] Currently, there are EZH2 inhibitors in clinical development, which are briefly listed below: 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.

[0006] 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).

[0007] In addition, primary aromatic amino groups are present in pharmaceuticals, 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 nitroarenes using iron catalysts, Pd-catalyzed Buchwald-Hartwig coupling of halogenated aromatics, Chan-Lam amination of boron compounds, Ni-catalyzed decarbonization 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.

[0008] However, these methods have drawbacks, 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.

[0009] Kengo Hyodo et al. (Org. Lett. 2019, 21, 8, 2818–2822) reported a novel method for preparing primary amines, using a novel oxime reagent as an amination agent. However, the oxime reagent is expensive to prepare, is an oily substance at room temperature that is difficult to store, and has a low conversion rate to aniline.

[0010] Summary of the Invention

[0011] On the one hand, the present disclosure provides a method for preparing a primary amine compound represented by formula (BI), 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.

[0012] R is optionally substituted with one or more substituents, such as aryl or C1-C 10 Alkyl, R' is selected from C1-C6 alkyl optionally substituted by one or more substituents, the ketone compound represented by formula (B-II) is such as acetophenone, p-methylacetophenone, p-methoxyacetophenone, p-chloroacetophenone, p-nitroacetophenone, 5-ethyl-2-methoxyacetophenone, benzyl acetone, acetylcyclohexane, 2-decanone,

[0013] The sulfonic acid amino ester is a compound represented by formula C or a salt thereof, wherein R1 is selected from a C1-C6 alkyl group, a C1-C6 alkyl group substituted with 1-3 halogen atoms, a C3-C6 cycloalkyl group and a phenyl group, and the phenyl group is optionally substituted with one or more substituents selected from a halogen, a cyano group, a nitro group, a C1-C6 alkyl group, and a C1-C6 alkyl group substituted with 1-3 halogen atoms; and R2 is selected from a hydrogen atom, a 2-trimethyl-silylethoxycarbonyl group (Teoc), a 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl group (Bpoc), a tert-butoxycarbonyl group (BOC), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc) and a benzyloxycarbonyl group (Cbz).

[0014] In some embodiments, the aforementioned substituents are independently selected from C1-C6 alkyl, halogen, deuterium, hydroxyl, thiol, -NR i R j , oxo, thio, -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, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic group, 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,

[0015] R i 、R j Each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group; R k independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, -NR i R j wherein the alkyl, alkoxy, and haloalkyl are optionally selected from C1 to C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thioxo, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl.

[0016] In some embodiments, the sulfonic acid amino ester is

[0017] In some embodiments, 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.

[0018] In some embodiments, the molar ratio of the ketone compound to the sulfonic acid amino ester is 1:1-1:3, for example, 1:1-1:2 or 1:1.1-1:1.5.

[0019] 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 etherate, 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.

[0020] 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.

[0021] In some embodiments, the solvent is one or more of lower alcohol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, n-hexane, and toluene. In some embodiments, the solvent is methanol or ethanol.

[0022] In some embodiments, the reaction temperature is between 0-60°C, such as 15-30°C, such as 40-50°C.

[0023] The preparation method disclosed in the present invention opens up a new low-cost and green approach for the preparation of amine compounds. Its advantages are 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 little pollution, and the yield is high.

[0024] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (A-II) or a salt thereof, comprising the steps 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:

[0025] X is a halogen, such as bromine;

[0026] R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, for example ethyl;

[0027] R2 is a carboxyl protecting group, such as C1-C6 alkyl, C6-C 10 an aryl group, such as a methyl or ethyl group;

[0028] 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.

[0029] In some embodiments, the metal catalyst is a combination of (Ph3P)2PdCl2 and CuI or a combination of Pd2(dba)3 and CuI. The molar ratio of (Ph3P)2PdCl2 or Pd2(dba)3 and CuI is 1:0.1-1:10, for example, 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 therebetween.

[0030] 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 PCy3, PCy3.HBF4, XantPhos, BINAP, dppf, Bu(Ad)2P, PPh3, Xphos, DavePhos, and CyJohnPhos, such as PCy3, 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.

[0031] In some embodiments, the reaction is carried out in the presence of a base, the base being selected from one or more of an inorganic base and an organic base, such as one or more of Cs2CO3, K3PO4, K2CO3, potassium acetate, potassium benzoate, DBU, prolinol, piperidine, triethylamine, diisopropylamine, pyridine, DIPEA, TMEDA, and TMPDA, such as a combination of Cs2CO3 and K3PO4, 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. In some embodiments, the base is a combination of Cs2CO3 and K3PO4. The molar ratio of Cs2CO3 and K3PO4 is 1:1-1:3, such as 1:1, 1:2, 1:3, or any value between the two.

[0032] 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 therebetween.

[0033] In some embodiments, the method further comprises the step of reacting a compound represented by formula (A-IV) to prepare a compound represented by formula (A-III), wherein R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, such as methyl,

[0034] 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.

[0035] In some embodiments, the reaction temperature is -20-30°C, eg, -10-10°C, 10-25°C.

[0036] 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).

[0037] In some embodiments, the reaction is carried out in the presence of an acid, a diazotizing agent, and an iodination agent. The acid is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride etherate, or trifluoroacetic acid; the diazotizing agent is preferably NaNO2, KNO2, isoamyl nitrite, or tert-butyl nitrite; and the iodination agent is preferably KI, NaI, TBAI, NIS, I(Py)2BF4, IOAC, KIO3, and IBr.

[0038] In some embodiments, the reaction temperature is -10-30°C.

[0039] 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).

[0040] In some embodiments, the reaction is carried out in the presence of an acid, a diazotizing agent, and an iodination agent. The acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride etherate, and trifluoroacetic acid, the diazotizing agent is selected from NaNO2, KNO2, isoamyl nitrite, and tert-butyl nitrite, and the iodination agent is selected from KI, NaI, TBAI, NIS, I(Py)2BF4, IOAC, KIO3, and IBr.

[0041] In some embodiments, the reaction temperature is -10-50°C.

[0042] In some embodiments, the method further comprises the step of reacting a compound represented by formula (AV) to prepare a 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,

[0043] 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-methylthiopropionate, ethyl 2-methylthioacetate, 3-methylthiopropanol, such as ethyl 3-methylthiopropionate; the Lewis acid is selected from boron chloride, boron bromide, boron iodide, dimethylboron bromide, aluminum chloride, aluminum bromide, methanesulfonic acid, preferably aluminum chloride.

[0044] In some embodiments, the reaction temperature is -20-35°C, eg, -10-10°C, 10-35°C.

[0045] 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).

[0046] In some embodiments, X is bromine, and the reaction is carried out in the presence of a brominating agent selected from HBr, Br2, NBS, DBDMH, HOBr, AcOBr, CF3COOBr, NH4Br, TBBDA, PBBS, tribromoisocyanurate, such as NBS, DBDMH.

[0047] In some embodiments, the reaction temperature is -10-30°C.

[0048] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (AI) or a salt thereof, the method comprising the steps of preparing a compound represented by formula (A-II) as described in the present disclosure, and deprotecting the compound represented by formula (A-II) to prepare a compound represented by formula (AI) or a salt thereof.

[0049] In some embodiments, the salt of the compound represented by formula (AI) 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.

[0050] Another aspect of 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 (AI) or a salt thereof as described in the present disclosure.

[0051] In some embodiments, the method further comprises the following steps,

[0052] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be prepared with reference to the methods disclosed in WO2019091450A and WO2023061467A, which are incorporated herein by reference in their entirety.

[0053] 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, isopropyl alcohol, propanol, ethanol, methanol, and water.

[0054] 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.

[0055] Another aspect of the present disclosure provides a compound represented by formula (A-II), wherein:

[0056] X is a halogen, such as bromine;

[0057] R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, for example ethyl;

[0058] R2 is a carboxyl protecting group, such as C1-C6 alkyl, C6-C 10 an aryl group, such as a methyl or ethyl group,

[0059] Another aspect of the present disclosure provides a compound represented by formula (A-III), wherein R1, R2, and X are as defined above,

[0060] Another aspect of the present disclosure provides a compound of formula (A-IV), wherein R1, R2, and X are as defined above, and R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, such as methyl.

[0061] Another aspect of the present disclosure provides a compound represented by formula (A-IV-1), wherein R1, R2, and X are as defined above,

[0062] Another aspect of the present disclosure provides a compound represented by formula (AV), wherein R1, R2, R3, and X are as defined above,

[0063] Another aspect of the present disclosure provides compound A-05,

[0064] 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.

[0065] In the preparation method disclosed in the present invention, the reactions connected by “→” refer to a one-step reaction to obtain the product.

[0066] 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 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 containing 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0067] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing 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 attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0068] "Carboxyl protecting group" is a suitable group for protecting carboxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the carboxyl protecting group, as an example, preferably, the carboxyl protecting group can be a substituted or unsubstituted C 1-10 Straight chain or branched alkyl, substituted or unsubstituted C 2-10 Straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 Alkyl or aryl) 3 silyl; preferably C 1-6 A straight or branched chain alkyl group, more preferably C 1-4 A straight chain or branched chain alkyl group, for example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0069] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0070] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that 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.

[0071] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, i.e. if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations.

[0072] 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

[0073] The present disclosure will be explained in detail below with reference to 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.

[0074] Reagents and abbreviations:

[0075] P / E: Petroleum ether / ethyl acetate

[0076] Example 1 Synthesis of 4-methylbenzenesulfonic acid (tert-butoxycarbonylamino) ester (Formula C1)

[0077] Tert-butyl N-hydroxycarbamate (100.0g, 0.75mol, 1.0eq) is dissolved in methyl tert-butyl ether (500mL), adds 4-methylbenzenesulfonyl chloride (143.2g, 0.75mol, 1.0eq), is transferred in ice bath, treats that the temperature in system drops to 5-10 ℃, drips triethylamine (79.8g, 0.79mol, 1.05eq), adds DMAP (4.6g, 37.5mmol, 0.05eq) and stirs 0.5h in ice bath simultaneously afterwards, warms to room temperature afterwards and stirs 4-5h. Monitor reaction by TLC and complete, filter, wash, and under reduced pressure concentrate organic phase. Crude product is beaten with petroleum ether (500mL), filter, and room temperature air-dry filter cake, obtain solid compound C1 201.0g altogether, productive rate is 88%.

[0078] Example 2 Synthesis of Compound A-03 (Using Compound C1)

[0079] 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·H2O (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. TLC detection showed that the raw material reaction was complete; most of the methanol was removed by rotary evaporation, and then 1 L of tert-methyl ether and NaOH ice water solution (100 g NaOH, 1.5 L ice water) were added to the system, stirred and separated, 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%.

[0080] Example 3 Synthesis of Compound B (Using Compound C1)

[0081] 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 a reaction flask and stirred to dissolve. A solution of TsOH·H2O (38.5 g, 202.4 mmol, 3.0 eq) in methanol (60 mL) was added to the stirred reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 16 h. TLC confirmed the complete reaction of the starting materials. Most of the methanol was removed by rotary evaporation. 100 mL of tert-methyl ether and an ice-cold NaOH solution (10 g NaOH, 150 mL ice water) were then added to the system. The mixture was stirred and separated. The aqueous phase was extracted once with tert-methyl ether (100 mL), and the organic phases were combined. The organic phases were 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%.

[0082] Example 4 Synthesis of Compound A-03 (using Compound D, a reagent used in Org. Lett. 2019, 21, 8, 2818–2822)

[0083] 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·H2O (1.1 g, 5.6 mmol, 0.1 eq) was added to the stirred reaction mixture at room temperature; the reaction was allowed to proceed at room temperature for 16 h. TLC detection showed that a small amount of raw material still remained; 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 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 4.4 g of compound A-03 with a yield of 52%.

[0084] Example 5 Synthesis of Compound A

[0085] Step 1: Synthesis of Compound A-01

[0086] To the reaction flask, p-ethylphenol (200 g, 1.64 mol) and DMAc (1.6 L) were added and stirred to dissolve until clear; then powdered K2CO3 (452 ​​g, 3.28 mol) and trimethyl phosphate (459 g, 3.28 mol) were added and stirred thoroughly to mix; the internal temperature of the reaction system was raised to 100°C and the reaction was allowed to proceed for 16-18 h; after TLC detection (P / E = 10:1) showed that the reaction was complete, heating was stopped and the reaction temperature was lowered to below 50°C; 3.2 L of water and 2.0 L of petroleum ether were added to the reaction system, the mixture was stirred for 0.5 h, and then allowed to stand to separate the liquids; the aqueous phase was extracted once with 1.0 L of petroleum ether, the organic phases were 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%.

[0087] Step 2: Synthesis of Compound A-02

[0088] 1.5 L of dichloromethane was added to the reaction flask, and AlCl3 (249 g, 1.87 mol) was added while stirring. The system was then placed at -10°C and A-01 (121 g, 0.89 mol) was slowly added. The system was then replaced with nitrogen three times; acetic anhydride (95 g, 0.93 mol) in dichloromethane (300 mL) was slowly dripped into the system and stirred for 10-20 min; after TLC detection (P / E = 10:1) showed that the reaction was complete, the system was slowly poured into 1 M HCl ice water solution (1.8 L) and stirred for 0.5 h; the mixture was allowed to stand and separated, and the aqueous phase was extracted once with 300 mL of dichloromethane. The organic phases were combined, washed once with 500 mL of brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 154 g of the title compound in a yield of 96%.

[0089] Step 3: Synthesis of Compound A-03

[0090] 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%.

[0091] Step 4: Synthesis of Compound A-04

[0092] Add 1.2 L of water, sodium sulfate (260 g, 1.83 mol), and chloral hydrate (78.4 g, 0.48 mol) 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 is started to be heated to 85 ° C, and an aqueous solution (180 mL) of hydroxylamine sulfate (90 g, 0.55 mol) is added and reacted for 4-5 hours; after TLC detection (P / E=4:1) 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, slurried at room temperature for 2-3 hours, and filtered to obtain 61 g of the intermediate with a yield of 75%.

[0093] 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. TLC detection (P / E = 2:1) shows that the reaction is complete; stop heating, cool to room temperature, and slowly pour into 2 L of ice water while stirring, and stir for 0.5 h; filter the precipitated solid, and dry it at 50°C to obtain 44 g of the title compound, with a yield of 95%.

[0094] Step 5: Synthesis of Compound A-05

[0095] 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 flask and stirred to mix evenly; the reaction system was placed in an ice bath and K2CO3 (52 g, 0.38 mol) was slowly added while stirring; after stirring in an ice bath for 0.5 h, 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% NaHSO3 solution (60 g, 0.57 mol) and 700 mL of petroleum ether were added to the reaction system while stirring; stirred thoroughly, and then 500 mL of water was added; the liquids were separated, and the aqueous phase was extracted once with 350 ml of petroleum ether, the liquids were separated, the organic phases were combined, the organic phases were washed once with 300 mL of brine, and dried over anhydrous sodium sulfate; filtered, and concentrated to remove the solvent to obtain 31.5 g of the title compound with a yield of 85% and a HPLC purity of 98%.

[0096] LC-MS: [M+H] + =210.11

[0097] 1H 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).

[0098] Step 6: Synthesis of Compound A-06

[0099] A-05 (28.7 g, 137.3 mmol) and 400 mL of acetone were added to the reaction flask, stirred to mix evenly, and placed in a -10--15°C cold trap. NBS (25.7 g, 144.2 mmol) was added, and the reaction was carried out at 0°C for 1-1.5 h. TLC detection (P / E = 6:1) showed that the reaction was complete; 150 mL of 10% NaHSO3 solution (15 g, 137.3 mmol) was added to the reaction system, stirred for 10-20 min, and 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, 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 an HPLC purity of 96%.

[0100] LC-MS: [M+H] + =288.02

[0101] 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).

[0102] Step 7: Synthesis of Compound A-07

[0103] A-06 (26.4 g, 91.6 mmol) and 225 mL of acetone were added to the reaction flask and stirred evenly; 184 mL of 3 M concentrated hydrochloric acid (549.4 mmol) was added to the system, stirred evenly, and the system was placed in ice water and stirred for 10-15 min; 46 mL of NaNO2 aqueous solution (12.6 g, 183.1 mmol) was slowly added dropwise thereto and stirred for 0.5 h; then 46 mL of KI aqueous solution (31.9 g, 192.3 mmol) was added dropwise thereto and continued to stir in ice water for 0.5-1 h, the system was transferred to room temperature and stirred for 16-18 h; after the reaction was complete by TLC detection (P / E=8:1), 200 mL of 10% NaHSO3 solution (20 g, 192.3 mmol), stirred for 10-20 min, then added 200 mL of water and 400 mL of tert-methyl ether, stirred for 10-20 min; separated, the aqueous phase was extracted once with 300 mL of tert-methyl ether, separated, 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 an HPLC purity of 98%.

[0104] MS: m / z = 397.90

[0105] 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).

[0106] Step 8: Synthesis of Compound A-08

[0107] 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 stirred to dissolve until clear. The system was purged with nitrogen and then placed in a cold trap at -10°C to -20°C. A 1 M boron trichloride dichloromethane solution (6.31 g, 53.9 mmol) was slowly added dropwise. The mixture was then reacted at 0°C for 16-18 h. TLC analysis (P / E = 5:1) indicated that the reaction was complete and the internal temperature of the system was lowered to 10°C. At about -10°C, 20 mL of methanol was added to quench the reaction, and the system was then transferred to room temperature and stirred for 0.5 h; 200 mL of dichloromethane and 100 mL of 10% NaHSO3 aqueous solution were added to the system, the layers were separated, and the aqueous phase was extracted with 150 mL of dichloromethane; the organic phases were combined, washed once with 200 mL of ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (P / E = 5%-10%); 8.2 g of the title compound was obtained with a yield of 99% and an HPLC purity of 99%.

[0108] LC-MS: [MH] - =382.89

[0109] 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).

[0110] Step 9: Synthesis of Compound A-09

[0111] 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-necked flask and stirred to mix uniformly; 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 and reacted for 16 h. The reaction was completed 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% The residue was washed with NaHCO3 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 give 3.7 g of the title compound with a yield of 65% and an HPLC purity of 98%.

[0112] LC-MS: [M+H] + =380.08

[0113] 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).

[0114] Step 10: Synthesis of Compound A

[0115] A-09 (2.5 g, 6.6 mmol) and 20 mL of ethanol were added to the reaction flask and stirred to dissolve until clear; 10 mL of NaOH (0.8 g, 19.8 mmol) solution was added to the system, the temperature was raised to 65°C, and the reaction was carried out for 6-8 h; TLC detection (P / E = 1:1) showed that the reaction was complete and heating was stopped; ethanol was removed, 13 mL of 6 M HCl was added to the system, stirred at 40°C for 1.5 h, filtered, and rinsed with purified water; 5 V of acetone was added to the residue, slurried for 0.5 h, filtered, and dried to obtain 2.3 g of the title compound with a yield of 95% and an HPLC purity of 98%.

[0116] LC-MS: [MH] - =364.06

[0117] 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 = 7.2Hz), 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=3.8Hz).

[0118] Example 6

[0119] Step 1: Synthesis of compound A-07-1

[0120] 260 mL of dichloromethane and AlCl3 (83.3 g, 624 mmol) were added to the reaction flask and the temperature was cooled to 10°C. A dichloromethane solution (130 mL) of A-06 (30 g, 104 mmol) was added dropwise to the reaction system and stirred. A dichloromethane solution (60 ml) of ethyl 3-methylthiopropionate (18.5 g, 125 mmol) was added dropwise to the reaction system and then transferred to a 37°C oil bath and stirred overnight. After the reaction was complete, the reaction system was slowly poured into 1.2 L of 20% sodium citrate (242 g, 936 mmol) in ice water and stirred. The pH of the system was adjusted to about 6-7 with NaOH, 400 mL of dichloromethane was added and stirred, and the liquid was separated. The organic phase was washed once with water, dried over anhydrous Na2SO4, filtered, and rotary evaporated to give a crude product, which was slurried with petroleum ether and filtered to give 20.6 g of the title product with a yield of 71% and a purity of 98%.

[0121] LC-MS: [M+H] + =274.11

[0122] 1H 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).

[0123] Step 2: Synthesis of Compound A-08

[0124] A-07-1 (26.4 g, 91.6 mmol) and 265 mL of acetone were added to the reaction flask and stirred evenly; 130 mL of dilute sulfuric acid (274.8 mmol) was added to the system and stirred evenly. The system was placed in ice water and stirred. 65 mL of NaNO2 aqueous solution (6.3 g, 91.6 mmol) was slowly added dropwise thereto. Then, 65 mL of KI aqueous solution (24.3 g, 146.6 mmol) was added dropwise thereto and continued stirring 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% NaHSO3 solution (20 g, 192.3 mmol), then add 200 mL of water and 400 mL of tert-methyl ether, separate the liquids, extract the aqueous phase once with 300 mL of tert-methyl ether, combine the organic phases, wash the organic phase once with 200 mL of brine, and dry over anhydrous sodium sulfate; concentrate and purify by column chromatography (P / E = 2.5%-5%) to obtain 35.2 g of the title compound with a yield of 96% and an HPLC purity of 98%.

[0125] Step 3: Synthesis of Compound A-09

[0126] 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), and Pd2(dba)3 (71.4 mg, 0.078 mmol) were then added in sequence, stirred evenly, and sealed. The mixture was replaced with nitrogen bubbling for 30-40 min, and then dissolved in 5 ml toluene / acetonitrile = 5:1 PCy3 (218 mg , 0.78 mmol) (nitrogen protection) was added to the reaction system via a syringe, and the reaction was carried out at 100° C. overnight. TLC monitoring (P / E=4:1) showed that the basic reaction was complete. The reaction solution was filtered through diatomaceous earth and rinsed with 200 ml of ethyl acetate; 300 ml of water was added to the filtrate, washed, and separated, and the aqueous phase was extracted twice with 150 ml of ethyl acetate; the organic phases were combined, washed once with 300 ml of brine, separated, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 11 g of a crude product; purified by column chromatography (P / E=5%-15%) to obtain 8.4 g of the title compound with a yield of 85% and an HPLC purity of 98%.

[0127] While the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to one skilled in the art and are intended to be included within the scope of this disclosure.

Claims

1. A method for preparing a primary amine compound represented by formula (BI), comprising the step 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 aryl or C1-C 10 alkyl, R' is selected from C1-C6 alkyl 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, 2. 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.

3. 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.

4. The preparation method according to any one of claims 1 to 3, wherein the reaction solvent is one or more of lower alcohols, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ether, methyl tert-butyl ether, n-hexane, and toluene, preferably methanol or ethanol.

5. 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; R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably ethyl; R2 is a carboxyl protecting group, preferably a C1-C6 alkyl, C6-C 10 Aryl, more preferably methyl or ethyl, 6. 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 the molar ratio of the compound shown in the preferred formula (A-III) to the metal catalyst is 1:0.001-1:0.

2.

7. The preparation method according to claim 5, wherein the metal catalyst is a combination of (Ph3P)2PdCl2 and CuI or a combination of Pd2(dba)3 and CuI, and preferably the molar ratio of (Ph3P)2PdCl2 or Pd2(dba)3 and CuI is 1:0.1-1:

10.

8. according to the preparation method described in any one of claims 5-7, 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 PCy3, PCy3.HBF4, XantPhos, BINAP, dppf, Bu(Ad)2P, PPh3, Xphos, DavePhos, and CyJohnPhos, most preferably PCy3, and the molar ratio of the compound represented by the preferred formula (A-III) to the phosphine ligand is 1:0.01-1:0.

5.

9. according to the preparation method described in any one of claims 5-8, wherein the reaction is carried out in the presence of a base, the base is preferably one or more of an inorganic base and an organic base, more preferably one or more of Cs2CO3, K3PO4, K2CO3, potassium acetate, potassium benzoate, DBU, prolinol, piperidine, triethylamine, diisopropylamine, pyridine, DIPEA, TMEDA, TMPDA, most preferably a combination of Cs2CO3 and K3PO4, and the molar ratio of the compound shown in the preferred formula (A-III) to the base is 1:1-1:

5.

10. The preparation method according to any one of claims 5 to 9, wherein the method further comprises the step of preparing a compound of formula (A-III) by reacting a compound of formula (A-IV), wherein R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably methyl, 11. The preparation method according to claim 10, wherein the reaction is carried out in the presence of a nucleophilic reagent and a Lewis acid, wherein the nucleophilic reagent is preferably tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylmercaptopropionate, ethyl 2-methylmercaptoacetate, 3-methylmercaptopropanol, and more preferably tetrabutylammonium iodide; and the Lewis acid is preferably boron chloride, boron bromide, boron iodide, dimethyl boron bromide, aluminum chloride, aluminum bromide, and more preferably boron chloride.

12. The preparation method according to any one of claims 10 to 11, further comprising the step of preparing a 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, or trifluoroacetic acid; the diazotizing agent is preferably NaNO2, KNO2, isopentyl nitrite, or tert-butyl nitrite; the iodizing agent is preferably KI, NaI, TBAI, NIS, I(Py)2BF4, IOAC, KIO3, and IBr, 13. The preparation method according to any one of claims 5 to 9, wherein the method further comprises the step of preparing a 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)2BF4, IOAC, KIO3 and Ibr, 14. The preparation method according to claim 13, further comprising the step of preparing a compound of formula (A-IV-1) by reacting a compound of formula (AV), wherein R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably methyl, 15. The preparation method according to claim 14, wherein the reaction is carried out in the presence of a nucleophilic reagent and a Lewis acid, wherein the nucleophilic reagent is preferably tetrabutylammonium iodide, NIS, KI, NaI, IBr, dimethyl sulfide, diethyl sulfide, ethanethiol, ethanedithiol, methionine, ethyl 3-methylmercaptopropionate, ethyl 2-methylmercaptoacetate, 3-methylmercaptopropanol, and more preferably ethyl 3-methylmercaptopropionate; and the Lewis acid is preferably boron chloride, boron bromide, boron iodide, dimethyl boron bromide, aluminum chloride, aluminum bromide, methanesulfonic acid, and more preferably aluminum chloride.

16. The preparation method according to claim 12 or 14, further comprising the step of preparing a compound of formula (AV) by reacting a compound of formula (A-VI), 17. 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.

18. A method for preparing a compound of formula (AI) or a salt thereof, the method comprising the step of preparing a compound of formula (A-II) according to any one of claims 5 to 17, and the step of preparing a compound of formula (AI) or a salt thereof by deprotecting the compound of formula (A-II).

19. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of preparing a compound of formula (AI) or a salt thereof according to claim 18, 20. 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, in, X is halogen, preferably bromine; R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably ethyl; R2 is a carboxyl protecting group, preferably a C1-C6 alkyl, C6-C 10 Aryl, preferably methyl or ethyl, R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, preferably methyl.