Preparation method for key intermediate of e3 ubiquitin ligase ligand

Abstract

The present invention relates to the technical field of drug synthesis methods, and relates to a preparation method for a key intermediate of an E3 ubiquitin ligase ligand. Specifically, the preparation method of the present invention comprises steps such as N-methylation, acylation, coupling, and substitution. Compared with preparation methods of the prior art, the present invention has a simple synthetic route, cheap raw materials, and a high yield, avoids the use of hazardous reagents, reduces the discharge of waste water, waste gas, and solid wastes, and is suitable for industrial production.

Description

A method for preparing a key intermediate of an E3 ubiquitin ligase ligand Technical Field

[0001] The invention belongs to the technical field of drug synthesis methods and relates to a method for preparing a key intermediate of an E3 ubiquitin ligase ligand. Background Art

[0002] KT-474, a protein targeting chimeras (PROTACs) targeting interleukin-1 receptor-associated kinase 4 (IRAK4) degrader developed by Kymera, targets IRAK4 through heterobifunctional molecule binding, recruiting the E3 ubiquitin ligase to "tag" IRAK4, thereby enabling its degradation via the proteasome. KT-474 exhibits high selectivity and oral bioavailability.

[0003] KT-474 is primarily designed to treat IL-1R / TLR-driven diseases, including hidradenitis suppurativa (HS) and atopic dermatitis (AD), as well as rheumatoid arthritis (RA) and other inflammatory diseases. IRAK4 mediates IL-1R / TLR downstream signaling through two pathways and participates in immune surveillance: First, IRAK4 has kinase activity, phosphorylating downstream proteins IRF5 / 7; second, IRAK4 acts as a scaffold, responsible for the assembly of protein multimers. Traditional small molecule inhibitors target only kinase activity, while KT-474 simultaneously blocks both kinase activity and scaffolding, thereby inhibiting the pathway and exerting strong anti-tumor activity. In preclinical studies, KT-474 has demonstrated potent anti-inflammatory activity. Phase 1 clinical trial results in healthy patients showed that a single dose of KT-474 dose-dependently reduced the levels of IRAK4 and various proinflammatory cytokines, with a favorable safety and tolerability profile.

[0004] Since the molecular structure of KT-474 also contains the E3 ubiquitin ligase ligand part, the compounds used to synthesize the above ligand part (for example, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione) may serve as key intermediates for the synthesis of KT-474.

[0005] CN116761633A discloses a synthetic route for 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VI). This route adopts a convergent route. First, 2-aminoglutaric acid is used as a starting material, and compound E is obtained through diazotization cyclization (S1), amidation (S2), ring expansion rearrangement (S3) and hydroxyl protection (S4). Then, 1-bromo-2-fluoro-3-nitrobenzene is used as a starting material, and compound I is obtained through substitution (S5), reduction (S6) and acylation (S7). Finally, compound E and compound I are reacted through substitution (S8) and amino deprotection (S9) to obtain the target product. The specific synthetic steps are as follows:

[0006] This route produces Compound VI via a nine-step reaction, resulting in a complex process and high costs, with a yield of only 4.2%. Furthermore, the use of thionyl chloride in the second step produces the hazardous gas sulfur dioxide; the third and eighth steps utilize potassium tert-butoxide, which is dangerous and explosive; the Bechamp reduction in the sixth step utilizes a large amount of iron, and the product is largely adsorbed onto iron powder and iron oxide, making it difficult to filter and purify, and the waste residue pollutes the environment; and the ninth step utilizes highly corrosive methanesulfonic acid and highly toxic toluene. Therefore, a new method for preparing the key intermediate of the IRAK degrader KT-474 is needed.

[0007] Summary of the Invention

[0008] Problems to be solved by the invention

[0009] In light of these challenges, the present invention aims to develop a method for preparing a key intermediate of an E3 ubiquitin ligase ligand. This method involves fewer steps, offers lower costs, and produces higher yields. Furthermore, this method avoids the use of hazardous, explosive, or toxic reagents and addresses waste gas emissions, making it suitable for commercial production.

[0010] Solutions for solving problems

[0011] Specifically, the present invention provides a method for preparing a key intermediate of IRAK degrader KT-474, which comprises the following steps:

[0012] 1) Compound I reacts with a methylating agent to obtain compound II,

[0013] 2) Compound II reacts with an acylating agent to obtain compound III,

[0014] 3) Compound III reacts with tert-butyl 4,5-diamino-5-oxopentanoate to obtain compound IV,

[0015] 4) Compound IV is reacted to obtain compound V,

[0016] 5) Compound V is reacted to obtain compound VI,

[0017] wherein R is selected from halogen, alkyl, aryl, nitro, cyano and amide.

[0018] Preferably, the alkyl group is C1-C 20 Alkyl, preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl.

[0019] Preferably, the aryl group is C6-C 20 Aryl, preferably C6-C 15 Aryl, more preferably C6-C 10 Aryl.

[0020] Preferably, the amide group is -NH-C(=O)-R', wherein R' is selected from hydrogen, C1-C 20 Alkyl and C6-C 20 Aryl, preferably hydrogen, C1-C 10 Alkyl and C6-C 15 Aryl, more preferably hydrogen, C1-C6 alkyl and C6-C 10 As the aryl group, hydrogen, methyl and phenyl are further preferred.

[0021] Preferably, in the compound of the preparation method, R is halogen, preferably bromine.

[0022] Preferably, the compound I in the preparation method is compound IA or compound IB,

[0023] Preferably, the methylating agent in step 1) is at least one of methyl iodide, methyl bromide, methyl chloride, a combination of paraformaldehyde and sodium borohydride, dimethyl sulfate and methyl methanesulfonate, preferably at least one of methyl iodide and a combination of paraformaldehyde and sodium borohydride.

[0024] Preferably, in step 1), when the methylating agent is methyl iodide, the molar ratio of the compound I to the methylating agent is 0.9:1 to 1:1.5, preferably 1:1.1.

[0025] Preferably, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the weight ratio of the compound I to the paraformaldehyde is 1:0.15 to 1:0.25, preferably 1:0.18.

[0026] Preferably, the reaction in step 1) is carried out in an organic solvent. Preferably, the organic solvent is at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably at least one of tetrahydrofuran and methanol, more preferably at least one of ultra-dry tetrahydrofuran and methanol.

[0027] Preferably, in step 1), the ratio of the compound I to the organic solvent is 1 g:10-1000 mL, preferably 1 g:14-620 mL.

[0028] Preferably, the reaction in step 1) is carried out in the presence of a base. Preferably, the base is an inorganic base, preferably at least one of sodium hydride, sodium methoxide, potassium tert-butoxide, tert-butyl lithium and lithium diisopropylamide, more preferably at least one of sodium hydride and sodium methoxide.

[0029] Preferably, in step 1), when the base is sodium hydride, the molar ratio of the compound I to the base is 0.9:1 to 1:1.5, preferably 1:1.1.

[0030] Preferably, in step 1), when the base is sodium methoxide, the molar ratio of the compound I to the base is 1:2 to 1:10, preferably 1:5.

[0031] Preferably, in step 1), when the methylating agent is iodomethane, the reaction temperature is -40°C to 50°C, preferably 0°C to room temperature.

[0032] Preferably, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the reaction temperature is -78°C to 100°C, preferably room temperature to 85°C.

[0033] Preferably, the reaction time in step 1) is 0.5 h to 24 h, preferably 7 h to 19 h.

[0034] Preferably, the acylating agent in step 2) is at least one of triphosgene, phosgene and N,N'-carbonyldiimidazole, preferably triphosgene.

[0035] Preferably, in step 2), the molar ratio of the compound II to the acylating agent is 1:0.4 to 1:0.6, preferably 1:0.5.

[0036] Preferably, the reaction in step 2) is carried out in an organic solvent. Preferably, the organic solvent is at least one of dichloromethane, dichloroethane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate and toluene, preferably dichloromethane.

[0037] Preferably, in step 2), the usage ratio of the compound II to the organic solvent is 1 g:3-100 mL, preferably 1 g:10-18 mL.

[0038] Preferably, the reaction in step 2) is carried out in the presence of a base, preferably, the base is an organic base, preferably at least one of pyridine, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride and sodium bicarbonate, more preferably pyridine.

[0039] Preferably, in step 2), the molar ratio of the compound II to the base is 1:1 to 1:15, preferably 1:2 to 1:6.

[0040] Preferably, the reaction temperature in step 2) is -80°C to 50°C, preferably -30°C to room temperature.

[0041] Preferably, the reaction time in step 2) is 0.5 h to 24 h, preferably 5.5 h to 6.5 h.

[0042] Preferably, in step 3), the molar ratio of compound III to tert-butyl 4,5-diamino-5-oxopentanoate is 1:0.9 to 1:3, preferably 1:1.1 to 1:1.2.

[0043] Preferably, the reaction in step 3) is carried out in an organic solvent. Preferably, the organic solvent is at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, dichloroethane and dimethyl sulfoxide, preferably acetonitrile.

[0044] Preferably, in step 3), the usage ratio of the compound III to the organic solvent is 1 g:4-100 mL, preferably 1 g:11-19 mL.

[0045] Preferably, the reaction in step 3) is carried out in the presence of a base, preferably, the base is an organic base, preferably at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, sodium bicarbonate, potassium carbonate and cesium carbonate, more preferably triethylamine.

[0046] Preferably, in step 3), the molar ratio of the compound III to the base is 1:1 to 1:5, preferably 1:2 to 1:2.5.

[0047] Preferably, the reaction in step 3) is carried out in the presence of a catalyst. Preferably, the catalyst is at least one of 4-dimethylaminopyridine and 1,4-diazabicyclo[2.2.2]octane, preferably 4-dimethylaminopyridine.

[0048] Preferably, in step 3), the molar ratio of the compound III to the catalyst is 1:0.01 to 1:0.2, preferably 1:0.03.

[0049] Preferably, the reaction temperature in step 3) is from room temperature to 110°C, preferably from room temperature to 75°C.

[0050] Preferably, the reaction time in step 3) is 1 h to 24 h, preferably 15.5 h to 16 h.

[0051] Preferably, the reaction in step 4) is carried out in an organic solvent. Preferably, the organic solvent is at least one of dimethyl sulfoxide, acetonitrile, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide, preferably dimethyl sulfoxide.

[0052] Preferably, in step 4), the ratio of compound IV to the organic solvent is 1 g: 3 to 50 mL, preferably 1 g: 8 to 10 mL.

[0053] Preferably, the reaction in step 4) is carried out in the presence of a base, preferably, the base is an organic base, preferably at least one of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,4-diazabicyclo[2.2.2]octane, more preferably 1,8-diazabicycloundec-7-ene.

[0054] Preferably, in step 4), the molar ratio of compound IV to the base is 1:1 to 1:3, preferably 1:1.5 to 1:2.

[0055] Preferably, the reaction in step 4) is carried out in the presence of a catalyst. Preferably, the catalyst is at least one of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper-cuprous oxide and copper-cuprous iodide, preferably at least one of cuprous oxide and cuprous iodide, more preferably cuprous oxide.

[0056] Preferably, in step 4), the molar ratio of compound IV to the catalyst is 1:0.05 to 1:1.5, preferably 1:0.2.

[0057] Preferably, the reaction in step 4) is carried out under nitrogen protection.

[0058] Preferably, the reaction temperature in step 4) is 60°C to 150°C, preferably 80°C to 130°C.

[0059] Preferably, the reaction time in step 4) is 0.2 h to 24 h, preferably 1 h to 3 h.

[0060] Preferably, the reaction in step 5) is carried out in an organic solvent. Preferably, the organic solvent is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, acetic acid and methanol, preferably acetonitrile.

[0061] Preferably, in step 5), the ratio of compound V to the organic solvent is 1 g:4-100 mL, preferably 1 g:10-14 mL.

[0062] Preferably, the reaction in step 5) is carried out in the presence of an acid. Preferably, the acid is an organic acid, preferably one of p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, acetic acid and methanesulfonic acid, more preferably any one of p-toluenesulfonic acid and benzenesulfonic acid.

[0063] Preferably, in step 5), the molar ratio of the compound V to the acid is 1:1 to 1:5, preferably 1:2 to 1:3.

[0064] Preferably, the reaction temperature in step 5) is from room temperature to 130°C, preferably 80°C.

[0065] Preferably, the reaction time in step 5) is 1 h to 40 h, preferably 6 h to 16 h.

[0066] Effects of the Invention

[0067] 1. The method for preparing the key intermediate of the present invention has few synthetic steps, low cost, is suitable for commercial production, and has a high yield.

[0068] 2. Compared with the original research route, the preparation method of the key intermediate of the present invention not only avoids the harmful gas sulfur dioxide produced by the use of thionyl chloride in the reaction, but also avoids the use of dangerous and explosive potassium tert-butoxide, highly corrosive methanesulfonic acid and highly toxic toluene. It also avoids the problems of most products being adsorbed on iron powder and iron oxide during ferric acid reduction, making purification difficult and the waste residue generated polluting the environment. DETAILED DESCRIPTION

[0069] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0070] In addition, numerous specific details are provided in the following detailed description to better illustrate the present invention. Those skilled in the art will appreciate that the present invention can be practiced without certain specific details. In other instances, methods, means, equipment, and steps well known to those skilled in the art are not described in detail in order to highlight the main points of the present invention.

[0071] Unless otherwise stated, the units used in this specification are international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0072] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0073] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "embodiments," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0074] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0075] In this specification, when "normal temperature" or "room temperature" is used, the temperature may be 10-40°C.

[0076] The present invention provides a method for preparing a key intermediate of IRAK degradation agent KT-474, which comprises the following steps:

[0077] 1. A method for preparing compound VI, comprising the following steps:

[0078] 1) Compound I reacts with a methylating agent to obtain compound II,

[0079] 2) Compound II reacts with an acylating agent to obtain compound III,

[0080] 3) Compound III reacts with tert-butyl 4,5-diamino-5-oxopentanoate to obtain compound IV,

[0081] 4) Compound IV is reacted to obtain compound V,

[0082] 5) Compound V is reacted to obtain compound VI,

[0083] Wherein, R can be selected from halogen, alkyl, aryl, nitro, cyano and amide.

[0084] Preferably, the alkyl group may be C1-C 20Alkyl, preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl.

[0085] Preferably, the aryl group may be C6-C 20 Aryl, preferably C6-C 15 Aryl, more preferably C6-C 10 Aryl.

[0086] Preferably, the amide group may be -NH-C(=O)-R', wherein R' is selected from hydrogen, C1-C 20 Alkyl and C6-C 20 Aryl, preferably hydrogen, C1-C 10 Alkyl and C6-C 15 Aryl, more preferably hydrogen, C1-C6 alkyl and C6-C 10 As the aryl group, hydrogen, methyl and phenyl are further preferred.

[0087] In one embodiment of the present invention, in the compound of the preparation method, R may be halogen.

[0088] In a preferred embodiment of the present invention, in the compound of the preparation method, R may be bromine.

[0089] In one embodiment of the present invention, the compound I in the preparation method may be compound IA or compound IB.

[0090] In one embodiment of the present invention, the methylating agent in step 1) may be at least one of methyl iodide, methyl bromide, methyl chloride, a combination of paraformaldehyde and sodium borohydride, dimethyl sulfate, and methyl methanesulfonate.

[0091] In a preferred embodiment of the present invention, the methylating agent in step 1) may be at least one of iodomethane, paraformaldehyde and sodium borohydride.

[0092] In one embodiment of the present invention, in step 1), when the methylating agent is iodomethane, the molar ratio of compound I to the methylating agent can be 0.9:1 to 1:1.5.

[0093] In a preferred embodiment of the present invention, in step 1), when the methylating agent is methyl iodide, the molar ratio of compound I to the methylating agent can be 1:1.1.

[0094] In one embodiment of the present invention, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the weight ratio of compound I to paraformaldehyde can be 1:0.15 to 1:0.25.

[0095] In a preferred embodiment of the present invention, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the weight ratio of compound I to paraformaldehyde can be 1:0.18.

[0096] In one embodiment of the present invention, the reaction in step 1) is carried out in an organic solvent, which can be at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

[0097] In a preferred embodiment of the present invention, the reaction in step 1) can be carried out in at least one of tetrahydrofuran and methanol.

[0098] In a more preferred embodiment of the present invention, the reaction in step 1) can be carried out in at least one of ultra-dry tetrahydrofuran and methanol.

[0099] In one embodiment of the present invention, the usage ratio of compound I to the organic solvent in step 1) can be 1 g:10-1000 mL.

[0100] In a preferred embodiment of the present invention, the usage ratio of compound I to the organic solvent in step 1) can be 1 g:14-620 mL.

[0101] In one embodiment of the present invention, the reaction in step 1) is carried out in the presence of a base, which may be an inorganic base, and the inorganic base may be at least one of sodium hydride, sodium methoxide, potassium tert-butoxide, tert-butyl lithium and lithium diisopropylamide.

[0102] In a preferred embodiment of the present invention, the reaction in step 1) can be carried out in the presence of at least one of sodium hydride and sodium methoxide.

[0103] In one embodiment of the present invention, in step 1), when the base is sodium hydride, the molar ratio of compound I to the base can be 0.9:1 to 1:1.5.

[0104] In a preferred embodiment of the present invention, in step 1), when the base is sodium hydride, the molar ratio of compound I to the base can be 1:1.1.

[0105] In one embodiment of the present invention, in step 1), when the base is sodium methoxide, the molar ratio of compound I to the base can be 1:2 to 1:10.

[0106] In a preferred embodiment of the present invention, in step 1), when the base is sodium methoxide, the molar ratio of compound I to the base can be 1:5.

[0107] In one embodiment of the present invention, in step 1), when the methylating agent is iodomethane, the reaction temperature can be -40°C to 50°C.

[0108] In a preferred embodiment of the present invention, in step 1), when the methylating agent is iodomethane, the reaction temperature can be from 0°C to room temperature.

[0109] In one embodiment of the present invention, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the reaction temperature may be -78°C to 100°C.

[0110] In a preferred embodiment of the present invention, in step 1), when the methylating agent is a combination of paraformaldehyde and sodium borohydride, the reaction temperature can be from room temperature to 85°C.

[0111] In one embodiment of the present invention, the reaction time in step 1) can be 0.5 h to 24 h.

[0112] In a preferred embodiment of the present invention, the reaction time in step 1) can be 7 h to 19 h.

[0113] In one embodiment of the present invention, the acylating agent in step 2) may be at least one of triphosgene, phosgene and N,N'-carbonyldiimidazole.

[0114] In a preferred embodiment of the present invention, the acylating agent in step 2) may be triphosgene.

[0115] In one embodiment of the present invention, the molar ratio of compound II to the acylating agent in step 2) can be 1:0.4 to 1:0.6.

[0116] In a preferred embodiment of the present invention, the molar ratio of compound II to the acylating agent in step 2) can be 1:0.5.

[0117] In one embodiment of the present invention, the reaction in step 2) is carried out in an organic solvent, which can be at least one of dichloromethane, dichloroethane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate and toluene.

[0118] In a preferred embodiment of the present invention, the reaction in step 2) can be carried out in dichloromethane.

[0119] In one embodiment of the present invention, the usage ratio of compound II to the organic solvent in step 2) can be 1 g:3-100 mL.

[0120] In a preferred embodiment of the present invention, the usage ratio of compound II to the organic solvent in step 2) can be 1 g:10-18 mL.

[0121] In one embodiment of the present invention, the reaction in step 2) is carried out in the presence of a base, which may be an organic base, which may be at least one of pyridine, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride and sodium bicarbonate.

[0122] In a preferred embodiment of the present invention, the reaction in step 2) can be carried out in the presence of pyridine.

[0123] In one embodiment of the present invention, the molar ratio of compound II to the base in step 2) can be 1:1 to 1:15.

[0124] In a preferred embodiment of the present invention, the molar ratio of compound II to the base in step 2) can be 1:2 to 1:6.

[0125] In one embodiment of the present invention, the reaction temperature in step 2) can be -80°C to 50°C.

[0126] In a preferred embodiment of the present invention, the reaction temperature in step 2) can be from -30°C to room temperature;

[0127] In one embodiment of the present invention, the reaction time in step 2) can be 0.5 h to 24 h.

[0128] In a preferred embodiment of the present invention, the reaction time in step 2) can be 5.5 h to 6.5 h.

[0129] In one embodiment of the present invention, the molar ratio of compound III to tert-butyl 4,5-diamino-5-oxopentanoate in step 3) can be 1:0.9 to 1:3.

[0130] In a preferred embodiment of the present invention, the molar ratio of compound III to tert-butyl 4,5-diamino-5-oxopentanoate in step 3) can be 1:1.1 to 1:1.2.

[0131] In one embodiment of the present invention, the reaction in step 3) is carried out in an organic solvent, which can be at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, dichloroethane and dimethyl sulfoxide.

[0132] In a preferred embodiment of the present invention, the reaction in step 3) can be carried out in acetonitrile.

[0133] In one embodiment of the present invention, the usage ratio of compound III to the organic solvent in step 3) can be 1 g:4-100 mL.

[0134] In a preferred embodiment of the present invention, the usage ratio of compound III to the organic solvent in step 3) can be 1 g:11-19 mL.

[0135] In one embodiment of the present invention, the reaction in step 3) is carried out in the presence of a base, and the base is an organic base, which can be at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, sodium bicarbonate, potassium carbonate and cesium carbonate.

[0136] In a preferred embodiment of the present invention, the reaction in step 3) can be carried out in the presence of triethylamine.

[0137] In one embodiment of the present invention, the molar ratio of compound III to the base in step 3) can be 1:1 to 1:5.

[0138] In a preferred embodiment of the present invention, the molar ratio of compound III to the base in step 3) can be 1:2 to 1:2.5.

[0139] In one embodiment of the present invention, the reaction in step 3) is carried out in the presence of a catalyst, which may be at least one of 4-dimethylaminopyridine and 1,4-diazabicyclo[2.2.2]octane.

[0140] In a preferred embodiment of the present invention, the reaction in step 3) can be carried out in the presence of 4-dimethylaminopyridine.

[0141] In one embodiment of the present invention, the molar ratio of compound III to the catalyst in step 3) can be 1:0.01 to 1:0.2.

[0142] In a preferred embodiment of the present invention, the molar ratio of compound III to the catalyst in step 3) can be 1:0.03.

[0143] In one embodiment of the present invention, the reaction temperature in step 3) can be from room temperature to 110°C.

[0144] In a preferred embodiment of the present invention, the reaction temperature in step 3) can be from room temperature to 75°C.

[0145] In one embodiment of the present invention, the reaction time in step 3) can be 1 h to 24 h.

[0146] In a preferred embodiment of the present invention, the reaction time in step 3) can be 15.5 h to 16 h.

[0147] In one embodiment of the present invention, the reaction in step 4) is carried out in an organic solvent, which is at least one of dimethyl sulfoxide, acetonitrile, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

[0148] In a preferred embodiment of the present invention, the reaction in step 4) can be carried out in dimethyl sulfoxide.

[0149] In one embodiment of the present invention, the usage ratio of compound IV to the organic solvent in step 4) can be 1 g:3-50 mL.

[0150] In a preferred embodiment of the present invention, the usage ratio of compound IV to the organic solvent in step 4) can be 1 g:8-10 mL.

[0151] In one embodiment of the present invention, the reaction in step 4) is carried out in the presence of a base, which is an organic base. The organic base may be at least one of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,4-diazabicyclo[2.2.2]octane.

[0152] In a preferred embodiment of the present invention, the reaction in step 4) can be carried out in the presence of 1,8-diazabicycloundec-7-ene.

[0153] In one embodiment of the present invention, the molar ratio of compound IV to the base in step 4) can be 1:1 to 1:3.

[0154] In a preferred embodiment of the present invention, the molar ratio of compound IV to the base in step 4) can be 1:1.5 to 1:2.

[0155] In one embodiment of the present invention, the reaction in step 4) is carried out in the presence of a catalyst, which may be at least one of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper-cuprous oxide and copper-cuprous iodide.

[0156] In a preferred embodiment of the present invention, the reaction in step 4) is carried out in the presence of a catalyst, which may be at least one of cuprous oxide and cuprous iodide.

[0157] In a more preferred embodiment of the present invention, the reaction in step 4) may be carried out in the presence of cuprous oxide.

[0158] In one embodiment of the present invention, the molar ratio of compound IV to the catalyst in step 4) can be 1:0.05 to 1:1.5.

[0159] In a preferred embodiment of the present invention, the molar ratio of compound IV to the catalyst in step 4) can be 1:0.2.

[0160] In one embodiment of the present invention, the reaction in step 4) is carried out under nitrogen protection.

[0161] In one embodiment of the present invention, the reaction temperature in step 4) can be 60°C to 150°C.

[0162] In a preferred embodiment of the present invention, the reaction temperature in step 4) can be 80°C to 130°C.

[0163] In one embodiment of the present invention, the reaction time in step 4) can be 0.2 h to 24 h.

[0164] In a preferred embodiment of the present invention, the reaction time in step 4) can be 1 h to 3 h.

[0165] In one embodiment of the present invention, the reaction in step 5) is carried out in an organic solvent, which may be at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, acetic acid and methanol.

[0166] In a preferred embodiment of the present invention, the reaction in step 5) can be carried out in acetonitrile.

[0167] In one embodiment of the present invention, the ratio of compound V to the organic solvent in step 5) can be 1 g:4-100 mL.

[0168] In a preferred embodiment of the present invention, the usage ratio of compound V to the organic solvent in step 5) can be 1 g:10-14 mL.

[0169] In one embodiment of the present invention, the reaction in step 5) is carried out in the presence of an acid, which is an organic acid. The organic acid may be one of p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, acetic acid and methanesulfonic acid.

[0170] In a preferred embodiment of the present invention, the reaction in step 5) can be carried out in the presence of p-toluenesulfonic acid or benzenesulfonic acid.

[0171] In one embodiment of the present invention, the molar ratio of compound V to the acid in step 5) can be 1:1 to 1:5.

[0172] In a preferred embodiment of the present invention, the molar ratio of compound V to the acid in step 5) can be 1:2 to 1:3.

[0173] In one embodiment of the present invention, the reaction temperature in step 5) can be from room temperature to 130°C.

[0174] In a preferred embodiment of the present invention, the reaction temperature in step 5) may be 80°C;

[0175] In one embodiment of the present invention, the reaction time in step 5) can be 1 h to 40 h.

[0176] In a preferred embodiment of the present invention, the reaction time in step 5) can be 6 h to 16 h.

[0177] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0178] Example 1: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0179] Step 1: Synthesis of 2,6-dibromo-N-methylaniline

[0180] To a solution of 2,6-dibromoaniline (115 g, 0.458 mol) in ultra-dry THF (1.2 L) was slowly added portionwise NaH (60 wt% dispersion in mineral oil, 20.2 g, 0.504 mol) at 0°C. After the addition was complete, the reaction mixture was stirred at 0°C for 1 h. Then, CH3I (71.5 g, 0.504 mol) was added to the reaction mixture at 0°C. The resulting mixture was stirred at room temperature for 6 h. LCMS indicated complete reaction completion. The reaction mixture was poured into ice water (2.0 L) and extracted with EA (1.0 L x 3). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column (PE / EA = 20:1 to 10:1, v / v) to afford a light yellow oil (104.9 g, 86.4% yield).

[0181] 1H NMR (400MHz, DMSO-d6): δ7.50 (d, J = 8.0Hz, 2H), 6.69 (t, J = 7.9Hz, 1H), 4.51 (d, J = 5.9Hz, 1H), 2.84 (d, J = 5.7Hz, 3H). MS: m / z 266.0 [M+1] + .

[0182] Step 2: Synthesis of (2,6-dibromophenyl)(methyl)carbamoyl chloride

[0183] To a solution of triphosgene (58.7 g, 0.198 mol) in DCM (1.0 L) at -30°C was added pyridine (100 mL), and the reaction mixture was stirred at -30°C for 30 minutes. 2,6-Dibromo-N-methylaniline (104.9 g, 0.396 mol) was then slowly added to the -30°C reaction mixture. After the addition was complete, the mixture was warmed to room temperature and stirred at room temperature for 6 hours. LCMS indicated the reaction was complete. The reaction mixture was carefully quenched with 0.5N HCl (600 mL) and extracted with DCM (800 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (PE / EA = 20:1 to 10:1, v / v) to afford a pale yellow solid (84.5 g, yield: 65.2%).

[0184] 1 H NMR (400MHz, DMSO-d6): δ7.82(d,J=8.1Hz,2H),7.32(t,J=8.2Hz,1H),3.18(s,3H).MS:m / z 346.0[M+NH4] + .

[0185] Step 3: Synthesis of tert-butyl 5-amino-4-(3-(2,6-dibromophenyl)-3-methylureido)-5-oxopentanoate

[0186] To a solution of tert-butyl 4,5-diamino-5-oxopentanoate (57.3 g, 0.284 mol) in CH3CN (900 mL) at room temperature were added TEA (52.1 g, 0.516 mol) and DMAP (0.94 g, 7.74 mmol). The mixture was stirred at room temperature for 30 minutes. (2,6-Dibromophenyl)(methyl)carbamoyl chloride (84.5 g, 0.258 mol) was then slowly added to the reaction mixture. The resulting mixture was heated to 75°C and stirred for 15 hours. LCMS indicated that the reaction was complete. The reaction mixture was poured into water (1.0 L) and extracted with DCM (600 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column (DCM / MeOH = 20:1 to 10:1, v / v) to obtain a white solid (90.5 g, yield: 71.1%).

[0187] 1 H NMR (400MHz, DMSO-d6, 80℃): δ7.73(d,J=8.1Hz,2H),7.22(t,J=8.1Hz,1H),6.88(s,2H),5.40(s,1H),4.17-4.0 9(m,1H),3.02(s,3H),2.22-2.09(m,2H),1.99-1.83(m,1H),1.78-1.61(m,1H),1.36(s,9H).MS:m / z494.0[M+1] + .

[0188] Step 4: Synthesis of tert-butyl 5-amino-4-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate

[0189] To a solution of tert-butyl 5-amino-4-(3-(2,6-dibromophenyl)-3-methylureido)-5-oxopentanoate (90.5 g, 0.183 mol) in DMSO (700 mL) at room temperature was added CuO (5.25 g, 36.7 mmol) and DBU (41.7 g, 0.275 mol). The atmosphere was replaced with nitrogen 3-5 times, and the temperature was raised to 130°C with stirring for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was poured into water (2.0 L) and extracted with EA (700 mL*3). The combined organic layers were washed with brine (500 mL*3), dried over sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column (PE / EA = 3:1 to 3:2, v / v) to afford a white solid (70.8 g, yield: 93.6%).

[0190] 1H NMR (400MHz, DMSO-d6): δ7.42(s,1H),7.21(s,1H),7.18(dd,J=8.1,1.3Hz,1H),7.04-6.97(m,1H),6.96-6.88(m,1H),4.85(dd,J=9.9,4.3Hz, 1H),3.59(s,3H),2.40-2.24(m,1H),2.22-1.88(m,3H),1.27(s,9H).MS:m / z412.0[M+1] + .

[0191] Step 5: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0192] To a solution of tert-butyl 5-amino-4-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate (70.8 g, 0.172 mol) in CH3CN (700 mL) was added TsOH (88.7 g, 0.515 mol) at room temperature. The reaction mixture was stirred at 80°C for 16 hours. LCMS showed that the reaction was completely complete. The reaction mixture was cooled to room temperature, and a white solid precipitated from the solution. The mixture was filtered, and the filter cake was washed with NaHCO3 (aqueous solution, 100 mL*3) and CH3CN (100 mL*2) to give a white solid (36.0 g, yield: 62.0%).

[0193] 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H),7.21(d,J=8.1Hz,1H),7.13(d,J=7.9Hz,1H),6.95(t,J=8.0Hz,1H),5.38( dd,J=12.6,5.4Hz,1H),3.60(s,3H),2.92-2.78(m,1H),2.75-2.53(m,2H),2.03-1.93(m,1H).MS:m / z338.0[M+1] + .

[0194] Example 2: Synthesis of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0195] Step 1: Synthesis of 2,5-dibromo-N-methylaniline

[0196] 1,4-Dibromo-2-nitrotoluene (100 g, 0.356 mol) was dissolved in ethyl acetate (1500 mL), acetic acid (500 mL), and water (50 mL). The solution was then heated to 50°C, and iron powder (79.52 g, 1.424 mol) was added portionwise. The reaction mixture was stirred at 80°C for 3 h. After completion, the reaction was quenched with saturated aqueous Na2CO3 (1000 mL) and extracted three times with ethyl acetate (500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain 2,5-dibromoaniline as a white solid (85 g, 95% yield).

[0197] 1 H NMR (400MHz, CDCl3): δ7.24 (d, J=8.5Hz, 1H), 6.90 (d, J=2.2Hz, 1H), 6.73 (dd, J=8.4, 2.2Hz, 1H). MS: m / z 251.9 [M+1] + .

[0198] At room temperature, 2,5-dibromoaniline (20 g, 79.71 mmol), paraformaldehyde (3.59 g, 119.56 mmol), a methanol solution of sodium methoxide (30 g / 100 g, 21.53 g, 398.53 mmol), and methanol (200 mL) were added. The reaction mixture was stirred at room temperature for 16 h, then sodium borohydride (4.52 g, 119.56 mmol) was added and the temperature was raised to 85°C and stirring continued for 3 h. After completion of the reaction, the reaction was quenched with water (100 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (petroleum ether) to obtain a yellow oil (20.11 g, yield: 95%).

[0199] 1 H NMR (400MHz, CDCl3): δ7.24 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.68 (dd, J = 8.3, 2.2 Hz, 1H), 2.88 (s, 3H).

[0200] Step 2: Synthesis of (2,5-dibromophenyl)(methyl)carbamoyl chloride

[0201] At -30 ° C, under the protection of inert gas, a solution of triphosgene (16.8g, 56mmol) in DCM (350mL) was added dropwise a solution of pyridine (17.91g, 226mmol) in DCM (100mL). The reaction mixture was stirred at -30 ° C for 30min. Then a solution of 2,5-dibromo-N-methylaniline (30g, 113mmol) in DCM (100mL) was added dropwise. The mixture was warmed to room temperature and stirred at room temperature for 5 hours. After the reaction was completed, it was quenched with 1M hydrochloric acid (30mL) and water (200mL) and extracted three times with DCM (100mL). The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure to give a white solid (38g). It was used directly in the next step without further purification.

[0202] Step 3: Synthesis of tert-butyl 5-amino-4-(3-(2,5-dibromophenyl)-3-methylureido)-5-oxopentanoate

[0203] To a solution of (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (27.29 g, 136 mmol) in CH3CN (500 mL) was added TEA (28.59 g, 283 mmol). A solution of (2,6-dibromophenyl)(methyl)carbamoyl chloride (37 g, 113 mmol) in CH3CN (200 mL) was then added to the reaction mixture at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, the mixture was quenched with water (300 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (PE / EA = 2:1, v / v) to obtain a viscous, colorless solid (52 g, yield: 93%).

[0204] 1 H NMR (400MHz, CDCl3): δ7.54-7.45(m,2H),7.33(dd,J=8.6,2.4Hz,1H),6.81(s,1H),6.05(s,1H),4.34(t d,J=7.2,4.9Hz,1H),3.13(s,3H),2.29(qt,J=16.9,7.0Hz,2H),2.04-1.74(m,2H),1.35(s,9H).MS:m / z 494.0[M+1] + .

[0205] In this step of the reaction, (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride, (R)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride or their racemate can all be reacted.

[0206] Step 4: Synthesis of tert-butyl 5-amino-4-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate

[0207] To a solution of tert-butyl 5-amino-4-(3-(2,5-dibromophenyl)-3-methylureido)-5-oxopentanoate (52 g, 105 mmol) in DMSO (500 mL) was added Cu2O (4.02 g, 21 mmol) and DBU (32.1 g, 211 mmol) at room temperature. The mixture was heated to 80°C and stirred for 3 hours. After completion of the reaction, the mixture was quenched with 1 M hydrochloric acid (30 mL) and water (200 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (PE / EA=2:1, v / v) to give a white solid (36 g, yield: 82.8%).

[0208] Step 5: Synthesis of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0209] To a solution of tert-butyl 5-amino-4-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate (36 g, 87 mmol) in CH3CN (500 mL) was added benzenesulfonic acid (27.62 g, 175 mmol) at room temperature. The reaction mixture was stirred at 80°C for 6 hours. After completion of the reaction, the mixture was quenched with water (300 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and then triturated (PE / EA = 2:1, 300 mL) to give a white solid (25 g, yield: 84%).

[0210] Through the above steps, in the preparation method of the present invention, the total yield of Example 1 is 23.2%, and the total yield of Example 2 is 58.4%, which are significantly improved compared to the prior art. In the preparation process, the present invention not only uses stable, inexpensive, and simple-to-purify reagents such as iodomethane, DMAP, DBU, and p-toluenesulfonic acid, but also uses conventional reagents such as methanol, sodium hydride, and triphosgene, making it suitable for commercial production.

[0211] It should be noted that, although the technical solutions of the present invention are described with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0212] While various embodiments of the present invention have been described above, the above descriptions are intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing Compound VI, which comprises the following steps: 1) Compound I reacts with a methylation reagent to obtain Compound II, 2) Compound II reacts with an acylating agent to obtain Compound III, 3) Compound III reacts with tert-butyl 4,5-diamino-5-oxopentanoate to obtain Compound IV, 4) Compound IV undergoes a reaction to obtain Compound V, 5) The compound V is reacted to obtain the compound VI, Wherein, R is selected from halogen, alkyl, aryl, nitro, cyano and amide group; Preferably, R is halogen, preferably bromine; And / or, Preferably, Compound I is Compound IA or Compound IB, 2. The preparation method according to claim 1, wherein, In step 1), The methylation reagent is at least one of methyl iodide, methyl bromide, methyl chloride, the combination of paraformaldehyde and sodium borohydride, dimethyl sulfate and methyl methanesulfonate, preferably at least one of methyl iodide and the combination of paraformaldehyde and sodium borohydride; and / or, when the methylation reagent is methyl iodide, the molar ratio of Compound I to the methylation reagent is 0.9:1 to 1:1.5, preferably 1:1.1; and / or, when the methylation reagent is the combination of paraformaldehyde and sodium borohydride, the weight ratio of Compound I to paraformaldehyde is 1:0.15 to 1:0.25, preferably 1:0.

18.

3. The preparation method according to claim 1 or 2, characterized in that, In step 1), The reaction is carried out in an organic solvent; Preferably, the organic solvent is at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably at least one of tetrahydrofuran and methanol, more preferably at least one of ultra-dry tetrahydrofuran and methanol; and / or, the dosage ratio of Compound I to the organic solvent is 1 g:10 to 1000 mL, preferably 1 g:14 to 620 mL; And / or, The reaction is carried out in the presence of a base; Preferably, the base is an inorganic base, preferably at least one of sodium hydride, sodium methoxide, potassium tert-butoxide, tert-butyllithium and lithium diisopropylamide, more preferably at least one of sodium hydride and sodium methoxide; and / or, when the base is sodium hydride, the molar ratio of Compound I to the base is 0.9:1 to 1:1.5, preferably 1:1.1; and / or, when the base is sodium methoxide, the molar ratio of Compound I to the base is 1:2 to 1:10, preferably 1:5; And / or, When the methylation reagent is methyl iodide, the reaction temperature is -40°C to 50°C, preferably 0°C to room temperature; and / or, when the methylation reagent is the combination of paraformaldehyde and sodium borohydride, the reaction temperature is -78°C to 100°C, preferably room temperature to 85°C; And / or, The reaction time is 0.5 h to 24 h, preferably 7 h to 19 h.

4. The preparation method according to any one of claims 1 to 3, characterized in that, In step 2), The acylating reagent is at least one of triphosgene, phosgene and N,N'-carbonyldiimidazole, preferably triphosgene; and / or, the molar ratio of Compound II to the acylating reagent is 1:0.4 to 1:0.6, preferably 1:0.

5.

5. The preparation method according to any one of claims 1 to 4, characterized in that, In step 2), The reaction is carried out in an organic solvent; Preferably, the organic solvent is at least one of dichloromethane, dichloroethane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate and toluene, preferably dichloromethane; and / or, the dosage ratio of Compound II to the organic solvent is 1 g:3 to 100 mL, preferably 1 g:10 to 18 mL; And / or, The reaction is carried out in the presence of a base; Preferably, the base is an organic base, preferably at least one of pyridine, triethylamine, N,N - diisopropylethylamine, 4 - dimethylaminopyridine, sodium hydride, and sodium bicarbonate, more preferably pyridine; and / or, the molar ratio of Compound II to the base is 1:1 to 1:15, preferably 1:2 to 1:6; and / or, the temperature of the reaction is -80°C to 50°C, preferably -30°C to room temperature; and / or, the reaction time is 0.5 h to 24 h, preferably 5.5 h to 6.5 h.

6. The preparation method according to any one of claims 1 to 5, characterized in that In step 3), the molar ratio of Compound III to tert - butyl 4,5 - diamino - 5 - oxopentanoate is 1:0.9 to 1:3, preferably 1:1.1 to 1:1.

2.

7. The preparation method according to any one of claims 1 to 6, characterized in that, In step 3), the reaction is carried out in an organic solvent; Preferably, the organic solvent is at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4 - dioxane, N,N - dimethylformamide, N - methylpyrrolidone, dichloromethane, dichloroethane, and dimethyl sulfoxide, preferably acetonitrile; and / or, the dosage ratio of Compound III to the organic solvent is 1 g:4 to 100 mL, preferably 1 g:11 to 19 mL; and / or, the reaction is carried out in the presence of a base; Preferably, the base is an organic base, preferably at least one of triethylamine, N,N - diisopropylethylamine, pyridine, 4 - dimethylaminopyridine, 1,4 - diazabicyclo[2.2.2]octane, sodium bicarbonate, potassium carbonate, and cesium carbonate, more preferably triethylamine; and / or, the molar ratio of Compound III to the base is 1:1 to 1:5, preferably 1:2 to 1:2.5; and / or, the reaction is carried out in the presence of a catalyst; Preferably, the catalyst is at least one of 4 - dimethylaminopyridine and 1,4 - diazabicyclo[2.2.2]octane, preferably 4 - dimethylaminopyridine; and / or, the molar ratio of Compound III to the catalyst is 1:0.01 to 1:0.2, preferably 1:0.03; and / or, the temperature of the reaction is from room temperature to 110°C, preferably from room temperature to 75°C; and / or, the reaction time is 1 h to 24 h, preferably 15.5 h to 16 h.

8. The preparation method according to any one of claims 1 to 7, characterized in that, In step 4), the reaction is carried out in an organic solvent; Preferably, the organic solvent is at least one of dimethyl sulfoxide, acetonitrile, 1,4 - dioxane, N - methylpyrrolidone, N,N - dimethylformamide, and N,N - dimethylacetamide, preferably dimethyl sulfoxide; and / or, the dosage ratio of Compound IV to the organic solvent is 1 g:3 to 50 mL, preferably 1 g:8 to 10 mL; and / or, the reaction is carried out in the presence of a base; Preferably, the base is an organic base, preferably at least one of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, and 1,4-diazabicyclo[2.2.2]octane, more preferably 1,8-diazabicycloundec-7-ene; and / or, the molar ratio of the compound IV to the base is 1:1 to 1:3, preferably 1:1.5 to 1:2; and / or, the reaction is carried out in the presence of a catalyst; Preferably, the catalyst is at least one of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper-cuprous oxide, and copper-cuprous iodide, preferably at least one of cuprous oxide and cuprous iodide, more preferably cuprous oxide; and / or, the molar ratio of the compound IV to the catalyst is 1:0.05 to 1:1.5, preferably 1:0.2; and / or, the reaction is carried out under nitrogen protection; and / or, the temperature of the reaction is 60°C to 150°C, preferably 80°C to 130°C; and / or, the reaction time is 0.2 h to 24 h, preferably 1 h to 3 h.

9. The preparation method according to any one of claims 1 to 8, characterized in that, In step 5), the reaction is carried out in an organic solvent; Preferably, the organic solvent is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, acetic acid, and methanol, preferably acetonitrile; and / or, the dosage ratio of the compound V to the organic solvent is 1 g:4 to 100 mL, preferably 1 g:10 to 14 mL; and / or, the reaction is carried out in the presence of an acid; Preferably, the acid is an organic acid, preferably one of p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, acetic acid, and methanesulfonic acid, more preferably any one of p-toluenesulfonic acid and benzenesulfonic acid; and / or, the molar ratio of the compound V to the acid is 1:1 to 1:5, preferably 1:2 to 1:3; and / or, the temperature of the reaction is from room temperature to 130°C, preferably 80°C; and / or, the reaction time is 1 h to 40 h, preferably 6 h to 16 h.