A preparation method of nitrogen-containing heteroaromatic derivatives and intermediates thereof

Abstract

The present invention relates to a preparation method of nitrogen-containing heteroaromatic derivatives and intermediates thereof. The method of the present invention overcomes the defects existing in the prior art, greatly reduces the cost, and the obtained product has good purity, high yield, strong process operability and high process safety. Therefore, the method is suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of a nitrogen-containing heteroaromatic derivative, an intermediate thereof and an application thereof. Background Art

[0002] SHP-2 (Src homology-2 domain-containing phosphatase 2), also known as PTPN11 (tyrosine-protein phosphatase non-receptor type 11), is encoded by the PTPN11 gene and belongs to the protein tyrosine phosphatase (PTPs) family. As a downstream signaling molecule of cytokines, growth factors and other extracellular stimuli, SHP-2 is widely expressed in various tissues and cells of the body, participating in cell signal transduction, regulating cell growth, differentiation, migration, metabolism, gene transcription and immune response.

[0003] SHP-2 mainly consists of three components: SH-2 domain (N-SH2 and C-SH2), PTP active domain, and C-terminus (containing tyrosine phosphorylation site). The SH2 domain is highly conserved, is the phosphotyrosine binding site, and mediates the binding of the PTP domain to its ligand.

[0004] SHP-2 has two main states in the body: inactivated and activated. In the inactivated state, N-SH2 and PTP domain inside SHP-2 bind to each other, and because the PTP domain is occupied, SHP-2 is inactivated. When N-SH2 specifically binds to the phosphorylated tyrosine residue ligand, the PTP domain is exposed again and SHP-2 regains activity. According to the latest research, SHP-2 can also form dimers in the body, which can also lead to SHP-2 inactivation.

[0005] SHP-2 mainly functions by regulating signaling pathways such as ERK / MAPK, JAK-STAT, PI3K / AKT, Hippo, and Wnt / β-catenin, thereby maintaining the development of organisms and the dynamic balance in the body. Specific studies have shown that SHP-2 participates in the activation of the ERK / MAPK pathway by directly binding to receptor tyrosine kinases (RTKs) or scaffolds. In addition, activated SHP-2 can also recruit GRB2 / SOS, indirectly promoting the activation of the RAS signaling pathway. In addition, SHP-2 is also involved in signal transduction that inhibits immune responses. For example, SHP-2 and SHP-1 can bind to and activate immunosuppressive receptors (such as PD-1), blocking T cell activation.

[0006] As an important cell signaling factor, SHP-2 mutations are closely related to a variety of diseases. Studies have found that SHP-2 mutations are found in neuroblastoma, AML (4%), breast cancer, NSCLC (10%), lung adenocarcinoma (30%), esophageal cancer, head and neck tumors, melanoma, and gastric cancer.

[0007] The mutation sites of SHP-2 mostly occur in the N-SH2 and PTP active regions, which relieve the mutual inhibition of the N-CH2 / PTP domains and produce highly active SHP-2. Mutations such as Cys459Ser mutant and E76K mutant will affect the activity of SHP-2. Studies have shown that highly active SHP-2 is closely related to inflammation, cirrhosis, and the toxin CagA secreted by Helicobacter pylori, which can lead to the regeneration and development of tumors, equivalent to proto-oncogenes. With the deepening of our understanding of SHP-2, SHP-2 has been used as a target for tumor treatment for drug development.

[0008] Currently, several allosteric inhibitors of SHP-2 have entered the clinical research stage, such as TNO-155 developed by Novartis, RMC-4630 developed by Revolution Medicine, and JAB-3068 developed by Beijing Jacobs, which have entered the clinical phase I or phase II research stage. However, there is no SHP-2 inhibitor developed and marketed for the preparation and treatment of Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer. Therefore, it is urgent to develop a class of SHP-2 inhibitor drugs with good drugability.

[0009] PCT / CN2019 / 110314 discloses a nitrogen-containing heteroaromatic derivative inhibitor, its preparation method and application. The patent uses piperidine-4-carboxaldehyde derivatives and the like as raw materials to prepare nitrogen-containing heteroaromatic derivatives. However, due to the complex preparation steps and low overall yield, it is not suitable for large-scale industrial production. Summary of the invention

[0010] In order to solve the problems existing in the prior art, the inventors developed a method for preparing nitrogen-containing heteroaromatic derivatives during a long-term research and development process.

[0011] Specifically, the present invention provides a general formula ( ) is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0012] ;

[0013] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy or cyclopropyl;

[0014] R2 is selected from hydrogen or an amino protecting group; preferably hydrogen, acetyl, tert-butylsulfinyl, benzyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; more preferably tert-butyloxycarbonyl;

[0015] R3 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl or C 6-14 Aryl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro and C 1-6 Alkyl is substituted by one or more substituents; preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or C 6-12 Aryl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro and C 1-3 alkyl is substituted with one or more substituents; more preferably methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropyl or phenyl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro and C 1-3 The alkyl group is substituted with one or more substituents.

[0016] The present invention also provides a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0017] ;

[0018] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy or cyclopropyl;

[0019] R2 is selected from hydrogen or an amino protecting group; preferably hydrogen, acetyl, tert-butylsulfinyl, benzyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; more preferably tert-butyloxycarbonyl;

[0020] R3 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl or C 6-14 Aryl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro and C 1-6 Alkyl is substituted by one or more substituents; preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or C 6-12 Aryl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro and C 1-3 alkyl is substituted with one or more substituents; more preferably methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropyl or phenyl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro and C 1-3 The alkyl group is substituted by one or more substituents;

[0021] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy or cyclopropyl.

[0022] The present invention also provides a preparation method of the general formula ( ) is characterized by comprising the following preparation steps:

[0023] ;

[0024] The compound represented by the general formula (II) and the compound represented by the general formula (II-1) are heated to react in the presence of a titanate to obtain a compound represented by the general formula (III);

[0025] Wherein, R2 is selected from an amino protecting group, and the amino protecting group is selected from acetyl, tert-butylsulfinyl, benzyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; preferably tert-butyloxycarbonyl;

[0026] Optionally, the method further comprises a method for preparing the compound represented by general formula (II), characterized in that it further comprises the following steps:

[0027] ;

[0028] general formula( ) and the compound of the general formula ( -1) is reacted under alkaline conditions to obtain the general formula ( ) shown in the compound;

[0029] Wherein, X2 is selected from chlorine, bromine or iodine;

[0030] R1 and R3 are as defined in any of the above embodiments.

[0031] In a preferred embodiment of the present invention, in the method for preparing the compound represented by general formula (III):

[0032] The titanate is selected from ethyl titanate, isopropyl titanate, butyl titanate or tert-butyl titanate, preferably ethyl titanate;

[0033] The molar ratio of the compound represented by the general formula (II), the compound represented by the general formula (II-1) and the titanate is 1:1-2:1-2, preferably 1:1.2-2:1.5-2;

[0034] The reaction temperature is selected from 50~100 o C, preferably 60~80 o C, preferably 70-80 o C;

[0035] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably tetrahydrofuran, ethyl acetate or 1,4-dioxane;

[0036] In the method for preparing the compound represented by general formula (II):

[0037] The base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium or phenyllithium, preferably sodium tert-butoxide.

[0038] The reaction temperature is selected from 0~5 o C;

[0039] The general formula ( ) shown in the compound, the general formula ( -1) The molar ratio of the compound to the base is 1:1~2:1~2, preferably 1:1~1.5:1~1.5;

[0040] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably N,N-dimethylformamide.

[0041] The present invention also provides the general formula ( ) to prepare the compound of general formula (I ) is characterized by comprising the following preparation steps:

[0042] ;

[0043] general formula( ) and the compound represented by the general formula ( ) is reacted under alkaline conditions to obtain the general formula (I ) shown in the compound;

[0044] in,

[0045] X1 is selected from chlorine, bromine or iodine;

[0046] Optionally, it also comprises the same preparation formula as described in the above embodiment ( ) method for producing the compound shown;

[0047] R1, R2, R3 and R4 are as defined in any of the above embodiments.

[0048] In a preferred embodiment of the present invention, the preparation of the general formula (I ) in the method of:

[0049] The base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium or phenyllithium, preferably n-butyllithium;

[0050] The general formula ( -A) shown in the compound, the general formula ( ) The molar ratio of the compound to the base is 1:1-2:1-5, preferably 1:1.5-2:2-5;

[0051] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably tetrahydrofuran, ethyl acetate or 1,4-dioxane.

[0052] The present invention also provides a general formula (I ) to prepare the compound of general formula ( I) The method for preparing the compound is characterized by comprising the following preparation steps:

[0053] ;

[0054] General formula (I ) is reacted in the presence of GrubbsⅡ catalyst to obtain the general formula ( ) shown in the compound;

[0055] Optionally, further comprising preparing the general formula (I ) method for producing the compound shown;

[0056] Optionally, further comprising preparing the general formula ( ) method for producing the compound shown;

[0057] R1, R2, R3 and R4 are as defined in any of the above embodiments.

[0058] In a preferred embodiment of the present invention, the general formula (I ) The molar ratio of the compound to the catalyst is 1:0.02-0.1, preferably 1:0.06-0.1;

[0059] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably toluene.

[0060] The present invention also provides a preparation method of the general formula ( III) is characterized by comprising the following preparation steps:

[0061] ;

[0062] general formula( The compound represented by the general formula (X) and the compound represented by the general formula (VII) are heated under alkaline conditions to obtain the compound represented by the general formula (V I) the compound shown;

[0063] in,

[0064] X3 is selected from chlorine, bromine or iodine;

[0065] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0066] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0067] R7 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0068] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0069] Optionally, the method further comprises a method for preparing the compound represented by general formula (VII),

[0070] ;

[0071] general formula( ) is deprotected in an acid solution to obtain the general formula ( ) shown in the compound;

[0072] Optionally, further comprising preparing the general formula ( I) methods for the compounds shown;

[0073] Optionally, further comprising preparing the general formula (I ) method for producing a compound as shown;

[0074] Optionally, further comprising preparing the general formula ( ) method for producing a compound as shown;

[0075] R1, R2, R3 and R4 are as defined in any of the above embodiments;

[0076] Optionally, the general formula ( X) Preparation steps of the compound shown:

[0077] ;

[0078] The compound represented by the general formula (IX-3) and the compound represented by the general formula (IX-4) are reacted in the presence of a palladium catalyst and alkali A coupling reaction is carried out in the presence of to obtain a compound represented by the general formula (IX);

[0079] X5 is selected from chlorine, bromine or iodine;

[0080] Optionally, the general formula ( Preparation steps of the compound shown in X-3):

[0081] ;

[0082] The compound represented by the general formula (IX-2) is reacted with alkali In the presence of, under heating conditions, react in an anhydrous solvent to obtain a compound represented by the general formula (IX-3);

[0083] Optionally, the general formula ( Preparation steps of the compound shown in X-2):

[0084] ;

[0085] The compound represented by the general formula (IX-1) and 2-ethylhexyl 3-mercaptopropionate are reacted in the presence of a palladium catalyst. and alkali A coupling reaction is carried out in the presence of to obtain a compound represented by the general formula (IX-2);

[0086] X4 is selected from chlorine, bromine or iodine.

[0087] In a preferred embodiment of the present invention, in the preparation of the general formula (V I) In the preparation steps of the compound shown:

[0088] The base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride or lithium hydroxide, preferably potassium carbonate;

[0089] The general formula ( The molar ratio of the compound represented by formula (X), the compound represented by general formula (VII) and the base is 1:1-2:1-5, preferably 1:1-1.5:2-5;

[0090] The reaction temperature is selected from 50~100 o C, preferably 70~100 o C, preferably 80 to 100 o C;

[0091] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably N-methylpyrrolidone;

[0092] In the preparation of the general formula ( ) in the preparation steps of the compound shown in:

[0093] The acid is selected from hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid or nitric acid, preferably hydrochloric acid or trifluoroacetic acid;

[0094] The concentration of the acid is 1 to 5 M, preferably 2 to 3 M;

[0095] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably methanol;

[0096] In the preparation of the general formula ( X) In the preparation steps of the compound shown in

[0097] The palladium catalyst Selected from palladium acetate, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; preferably palladium acetate or tris(dibenzylideneacetone)dipalladium;

[0098] The base Selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate or cesium carbonate; preferably triethylamine, pyridine or N,N-diisopropylethylamine;

[0099] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane;

[0100] The compound represented by the general formula (IX-3), the compound represented by the general formula (IX-4) and the palladium catalyst The molar ratio is 1:1~2:0.02~0.1, preferably 1:1~1.5:0.05~0.1;

[0101] In the preparation of the general formula ( X-3) wherein:

[0102] The anhydrous solvent is selected from anhydrous methanol, anhydrous ethanol, anhydrous acetonitrile, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran or anhydrous 1,4-dioxane; preferably anhydrous ethanol;

[0103] The base Selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, n-butyl lithium, tert-butyl lithium or phenyl lithium, preferably sodium n-propoxide, sodium tert-butoxide or potassium tert-butoxide;

[0104] The heating temperature is selected from 50 to 100°C, preferably 50 to 70°C;

[0105] The compound represented by the general formula (IX-2) and a base The molar ratio is 1:1-2, preferably 1:1-1.5;

[0106] In the preparation of the general formula ( X-2) wherein:

[0107] The palladium catalyst Selected from palladium acetate, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; preferably palladium acetate or tris(dibenzylideneacetone)dipalladium;

[0108] The base Selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate or cesium carbonate; preferably triethylamine, pyridine or N,N-diisopropylethylamine;

[0109] The solvent is selected from ethyl acetate, dichloromethane, acetone, N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol or ethanol; preferably tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane;

[0110] The compound represented by the general formula (IX-1), 2-ethylhexyl 3-mercaptopropionate and a palladium catalyst The molar ratio is 1:1~2:0.02~0.1, preferably 1:1~1.5:0.05~0.1.

[0111] This process route has obvious advantages over the previous route:

[0112] 1. In the prior patent PCT / CN2019 / 110314, cyclization is first performed to form a spiro structure and then an amino substituent is introduced. This route first introduces an amino substituent and then cyclizes to form a spiro structure, which is a completely different route.

[0113] 2. The use of this route to prepare the spirocyclic intermediate greatly shortens the synthesis route, greatly improves the overall synthesis yield of the intermediate, and also greatly improves the yield of the final target product.

[0114] 3. This route has simple preparation steps, high total yield, low cost, and is suitable for large-scale industrial production.

[0115] Detailed description of the invention

[0116] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0117] "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 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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, etc.; the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment.

[0118] "Deuterated alkyl" means an alkyl group in which one or more hydrogen atoms are replaced by deuterium, wherein alkyl is as defined above.

[0119] "Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above; non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0120] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above; for example, trifluoromethyl.

[0121] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0122] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0123] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0124] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., and polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups; wherein the spirocyclic, condensed ring and bridged heterocyclic groups involved are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0125] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl; more preferably phenyl;

[0126] "Aryloxy" means an -O-(aryl) group in which aryl is as previously described.

[0127] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 members, more preferably 5 or 6 members, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridazinyl, pyrazinyl, oxadiazolyl, etc.

[0128] "Heteroaryloxy" refers to an -O-(heteroaryl) group in which heteroaryl is as previously described.

[0129] "Alkenyl" refers to a chain alkenyl group, also known as alkene wherein the alkenyl group may be further substituted by other relevant groups, for example: hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl or heteroaryloxy.

[0130] "Alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl or heteroaryloxy.

[0131] "Hydroxy" refers to an -OH group.

[0132] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0133] "Amino" refers to -NH2.

[0134] "Cyano" refers to -CN.

[0135] "Nitro" refers to -NO2.

[0136] "Alcohol solvents" refer to alkane compounds containing hydroxyl groups in the molecule, such as methanol, ethanol, and isopropanol.

[0137] "DCM" refers to dichloromethane.

[0138] "DIPEA" refers to N,N-diisopropylethylamine.

[0139] "DMF" refers to N,N-dimethylformamide.

[0140] "DMA" refers to N,N-dimethylacetamide.

[0141] "EA" refers to ethyl acetate.

[0142] "MTBE" means methyl tert-butyl ether.

[0143] "NMP" refers to N-methylpyrrolidone.

[0144] "n-BuLi" refers to n-butyllithium.

[0145] "THF" refers to tetrahydrofuran.

[0146] "Ti(OEt)4" refers to ethyl titanate.

[0147] In the present invention, the "plurality" in "plurality" or "multiples" refers to 1, 2, 3, 4, 5, 6, 7, etc.

[0148] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any one or more hydrogen atoms in the example compounds of the present invention can also be replaced by deuterium atoms. DETAILED DESCRIPTION

[0149] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0150] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0151] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 Infinity Series mass spectrometer.

[0152] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products are 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as a carrier.

[0153] The HPLC detection method in the present invention is as follows:

[0154]

[0155] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0156] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent.

[0157] Example 1

[0158] Preparation of 3-((3-chloro-2-aminopyridin-4-yl)thio)propionic acid (2-ethyl)hexyl ester

[0159] ;

[0160] Add 2-methyltetrahydrofuran (500 ml), 2-amino-3-chloro-4-iodopyridine (44.2 g), 3-mercaptopropionic acid-2-ethylhexyl ester (42.0 g), XantPhos (6.0 g), Pd(OAc)2 (1.9 g), DIPEA (45.0 g) to the reaction flask, start stirring, protect with nitrogen, heat to reflux, stir and react for 2 hours, take a sample for HPLC analysis, and the raw material reaction is complete. Cool to room temperature, add water (500 ml), add EA to extract twice, combine the organic phases, wash once with saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under vacuum to obtain a yellow solid. Add EA (200 ml) to the yellow solid, heat to 50°C, then slowly drip n-heptane (500 ml) to precipitate a solid, cool to room temperature, and stir for 1 hour. After filtration, the filter cake was pulled dry with an oil pump to obtain 56.0 g of a light yellow solid with a purity of 99.8% and a yield of 93.5%.

[0161] Example 2

[0162] Preparation of Potassium 3-Chloro-2-aminopyridine-4-thiolate

[0163] ;

[0164] Anhydrous ethanol (500 ml) and ethyl 3-((3-chloro-2-aminopyridin-4-yl)thio)propanoate (2-ethyl) (27.0 g) were added to the reaction flask, stirring was started, nitrogen protection was applied, potassium tert-butoxide (9.5 g) was added, and the temperature was raised to 50 °C for reaction for 2 hours. Sampling was performed, and HPLC was used to detect that the raw material reaction was complete. The ethanol was evaporated under reduced pressure, and then replaced with anhydrous THF once. The oil pump was pulled dry to obtain 36.4 g of yellow solid, which was directly used for the next step reaction.

[0165] Example 3

[0166] Preparation of 6-chloro-3-((3-chloro-2-aminopyridin-4-yl)thio)pyrazin-2-amine

[0167] ;

[0168] 2-Methyltetrahydrofuran (500 ml), potassium 3-chloro-2-aminopyridine-4-thiolate (36.4 g), 2-amino-3-bromo-6-chloropyrazine (16.0 g), Pd2(dba)3 (3.8 g), XantPhos (4.5 g), and DIPEA (20.3 g) were added to the reaction flask in sequence, and stirring was started and nitrogen protection was applied. The temperature was raised to reflux, and the reaction was carried out for 2 hours. Samples were taken and the reaction of the raw materials was detected by HPLC to be complete. The reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with EA, the filtrate was washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. Methanol (100 ml) was added to the crude product, the temperature was raised to 50 °C, water (30 ml) was added dropwise, stirred for 1 hour, slowly cooled to room temperature, and stirred for 1 hour. Filter, and the filter cake was pulled dry with an oil pump to obtain 14.5 g of a light green-brown solid with a purity of 96.8% and a two-step molar yield of 64.3%. 1 H-NMR (400 MHz, DMSO-d): δ 7.89(s, 1H), 7.70 (d, J =5.4 Hz, 1H), 7.17(s, 2H), 6.39(s, 2H), 5.96 (d, J = 5.3 Hz, 1H).

[0169] Example 4

[0170] Preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate

[0171] ;

[0172] DMF (800 ml) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (100 g) were added to the reaction flask, the system was cooled to 0°C, 54.1 g of sodium tert-butoxide solid was added, and the internal temperature was controlled to be less than 5°C. After the addition, stir for half an hour, then add 58.6 g of sodium tert-butoxide solid and stir for half an hour. Control the internal temperature to be less than 5°C, slowly add allyl bromide (56.7 g) to the system, and continue to stir for 1 hour after the drop is completed. Take a sample and monitor the complete reaction of the raw material by HPLC. Saturated NH4Cl aqueous solution (1000 ml) was added to the reaction system, and EA was added to extract twice, the organic phases were combined, washed once with saturated brine, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, drained, and the solvent was evaporated under reduced pressure to obtain 102 g of light yellow oil with a yield of 85.9%. 1H-NMR (400 MHz, CDCl3-d): δ9.50(s, 1H), 5.69-5.58(m, 1H), 5.12 (t, J=12 Hz, 2H), 3.79 (dt, J=14.0 Hz,0.44 Hz, 2H), 2.98-2.91(m, 2H), 2.26 (d, J=7.5 Hz, 2H), 1.94 (dt, J=14.4, 3.8Hz, 2H), 1.51-1.33 (m, 11H).

[0173] Example 5

[0174] Preparation of tert-butyl 4-allyl-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate

[0175] ;

[0176] Under nitrogen protection, THF (1000 ml), tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (70.6 g), (R)-tert-butylsulfenamide (40.5 g), Ti(OEt)4 (95.4 g) were added to the reaction flask in sequence, and the internal temperature was raised to 75 °C. The reaction was allowed to proceed for 3 hours. The reaction solution was tested by HPLC. The reaction of the raw materials was complete. The reaction solution was cooled to room temperature, diluted with 1000 ml EA, and water was slowly dripped into the reaction system to quench Ti(OEt)4. After the dripping was completed, the reaction system was stirred for 1 hour, filtered, and rinsed with EA. The organic phases were combined, washed twice with pure water, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-evaporated to remove the solvent to obtain 79.4 g of a light yellow solid with a yield of 80.0%. 1 H-NMR (400 MHz, CDCl3-d): δ 7.86(s, 1H), 5.66-5.61(m, 1H), 5.08-5.03(m, 2H), 3.74-3.76(m, 2H), 3.09-2.98(m, 2H), 2.27(d, J=7.5 Hz, 2H), 1.94(dt, J=14.4, 3.8Hz, 2H), 1.58(dt, J=14.4, 3.8 Hz, 2H), 1.44(s, 9H), 1.20(s, 9H).

[0177] Example 6

[0178] Preparation of 1-(bromovinyl)cyclopropane

[0179] ;

[0180] DCM (800 ml), cyclopropylacetylene (100.0 g), tetraethylammonium bromide (47.7 g) were added to the reaction flask, and then HBr aqueous solution (390 g) was added dropwise. After the addition was completed, the reaction was allowed to react at room temperature overnight. Samples were taken and sent to GC for detection. The raw materials reacted completely. The reaction system was cooled to 0-10 °C, and solid sodium carbonate was slowly added to the reaction system to adjust the system pH to 8. The temperature was then raised to room temperature, and the liquid was separated. The organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum with a water pump to remove DCM, and 171.3 g of a light yellow-brown liquid was obtained, with a GC purity of 96% and a yield of 77.0%.

[0181] Example 7

[0182] Preparation of tert-butyl 4-allyl-4-(1-((tert-butylsulfinyl)imino)-2-cyclopropylallyl)piperidine-1-carboxylate

[0183] ;

[0184] THF (800 ml), 1-(bromovinyl)cyclopropane (95.6 g), nitrogen protection were added to the reaction flask in sequence, and the temperature was lowered to -65 °C. 2.5M n-BuLi hexane solution (286 ml) was slowly added to the system, and after the addition was completed, the mixture was kept warm and stirred for 1 hour. In another single-mouth bottle, tert-butyl 4-allyl-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate (116.0 g) was dissolved in THF (350 ml), transferred to a constant pressure dropping funnel, and then slowly dripped into the above reaction solution, and after the dripping was completed, the mixture was kept warm and stirred for 1 hour. Samples were taken and sent to HPLC for detection. The raw material reacted completely. 800 ml of saturated brine was added to the system, and the mixture was heated to room temperature and stirred for half an hour. Separate the liquid, extract the aqueous phase once with EA, combine the organic phases, wash once with saturated brine, separate the layers, and dry the organic phase with anhydrous sodium sulfate. The mixture was filtered, rinsed with EA, and concentrated to dryness under vacuum to obtain 183.9 g of a light yellow oil, which was directly used in the next step.

[0185] Example 8

[0186] Preparation of tert-butyl (S)-1-((tert-butylsulfinyl)amino)-2-cyclopropyl-8-azaspiro[4.5]dec-2-ene-8-carboxylate

[0187] ;

[0188] Toluene (1800 ml) and tert-butyl 4-allyl-4-(1-((tert-butylsulfinyl)imino)-2-cyclopropylallyl)piperidine-1-carboxylate (183 g) were added to the reaction flask in sequence, stirred to dissolve, and then Grubbs II catalyst (22.1 g) was added, the temperature was raised to reflux, and the reaction was carried out for 24 hours. Samples were taken and sent to HPLC for analysis. The raw materials reacted completely. Cool to room temperature, filter (with a little diatomaceous earth), and rinse the filter cake with toluene. The filtrate was washed once with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum with a water pump to obtain a crude product. The crude product was stirred and dissolved with methanol (600 ml), activated carbon (25 g) was added, stirred for 2 hours, filtered, and the filter cake was rinsed with methanol (150 ml). The filtrate was concentrated to dryness under vacuum with a water pump. Add MTBE (100 ml) to the concentrate, heat to 55 °C and stir to dissolve, then slowly add petroleum ether (300 ml) dropwise, cool to 20-30 °C, keep warm and stir for 2 hours. Filter by suction, rinse the filter cake with petroleum ether, and vacuum dry to obtain 68.3 g of off-white solid, with a purity of 96.8% as determined by HPLC, and a two-step yield of 52.9%. 1 H-NMR (400 MHz, CDCl3-d): δ 5.213(s, 1H), 3.93-3.85(m,3H), 3.29(s, 1H), 2.88-2.85(m, 2H), 2.21-1.25(m, 25H), 0.73-0.64(m, 2H),0.45-0.38(m, 2H).

[0189] Example 9

[0190] Preparation of (S)-2-cyclopropyl-8-azaspiro[4.5]dec-2-en-1-amine dihydrochloride

[0191] ;

[0192] Tert-butyl (S)-1-((tert-butylsulfinyl)amino)-2-cyclopropyl-8-azaspiro[4.5]dec-2-ene-8-carboxylate (35 g) and methanol (175 ml) were added to the reaction bottle, and the hydrochloric acid dioxane solution (176 ml) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure. 50 ml of methanol was added to the concentrate, heated to dissolve, cooled to room temperature, and set aside. Take another reaction bottle, add tetrahydrofuran (500 ml), and the internal temperature was raised to 40-50 °C. The above methanol solution was slowly dripped into the reaction bottle containing tetrahydrofuran, and the solid slowly precipitated. The temperature was lowered to 20-30 °C and stirred for 2 hours. Filter and vacuum dry the filter cake to obtain 21.5 g of gray solid with a purity of 97% and a yield of 92.1%.

[0193] Example 10

[0194] Preparation of (S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-cyclopropyl-8-azaspiro[4.5]dec-2-en-1-amine

[0195] ;

[0196] Add (S)-2-cyclopropyl-8-azaspiro[4.5]dec-2-en-1-amine dihydrochloride (17.8 g), NMP (200 ml), K2CO3 (24.2 g) to the reaction flask, stir for half an hour, and then add 6-chloro-3-((3-chloro-2-aminopyridin-4-yl)thio)pyrazine-2-amine (15.5 g). Heat to 85 °C, react for 12 hours, take a sample, and analyze by HPLC. The raw material reacts completely. Cool to room temperature, add DCM (450 ml) and water (500 ml). After stirring, separate the liquids, and extract the aqueous phase once with DCM (300 ml). Combine the organic phases, wash twice with pure water, and then wash once with brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain a yellow semisolid. Add methanol (30 ml) to the semi-solid, heat to reflux, add EA (100 ml) dropwise, slowly cool to room temperature, and stir for 2 hours. Filter and vacuum dry the filter cake to obtain 19.6 g of light yellow solid with a purity of 98.1% and a yield of 81.7%. MS m / z(ESI): 444.1 [M+H] + ; 1 H-NMR (400 MHz, CDCl3-d): δ 7.67(d, J=5.4 Hz, 1H), 7.65(s, 1H), 6.05(d, J=5.4 Hz, 1H), 5.25 (s, 1H), 4.93 (s, 2H), 4.85 (s, 2H), 4.08-3.98 (m, 2H), 3.33 (s, 1H), 3.30-3.25 (m, 2H), 2.29 (d, J=16.2 Hz, 1H), 2.17(d, J=16.2 Hz, 1H), 1.81-1.25 (m, 7H), 0.81-0.65 (m, 2H), 0.55-0.42 (m, 2H).

Claims

1. A method for preparing compound (6), characterized in that: The preparation steps include: a) Compound (1-1) and Compound (1-2) react under alkaline conditions to obtain Compound (1); ； The base is sodium tert-butoxide; The molar ratio of the compound (1-1), the compound (1-2) and the base is 1:1~1.5:1~1.5; The reaction solvent is N,N-dimethylformamide; b) Compound (1) and Compound (2) are reacted by heating in the presence of a titanate to obtain Compound (3); ； The titanate is selected from ethyl titanate, isopropyl titanate, butyl titanate or tert-butyl titanate; The molar ratio of the compound (1), the compound (2) and the titanate is 1:1.2-2:1.5-2; The reaction temperature is 70~80 o C; c) Compound (3) reacts with compound (4) under alkaline conditions to obtain compound (5); ； The base is n-butyllithium; The molar ratio of the compound (3), the compound (4) and the base is 1:1.5-2:2-5; The reaction solvent is selected from tetrahydrofuran, ethyl acetate or 1,4-dioxane; d) Compound (5) is reacted in the presence of a Grubbs II catalyst to obtain compound (6); ； The molar ratio of the compound (5) to the catalyst is 1:0.06-0.1; The reaction solvent is toluene.

2. A method for preparing compound (9), characterized in that: The preparation steps include: a) Compound (8-1) is subjected to coupling reaction with 2-ethylhexyl 3-mercaptopropionate in the presence of a palladium catalyst ① and a base ① to obtain compound (8-2); ； X4 is selected from chlorine, bromine or iodine; b) Compound (8-2) reacts in the presence of base ② under heating conditions in an anhydrous solvent to obtain compound (8-3); ； c) Compound (8-3) and compound (8-4) undergo coupling reaction in the presence of a palladium catalyst ② and a base ③ to obtain compound (8); ； d) preparing compound (6) according to the method of claim 1; e) Compound (6) is deprotected in an acid solution to obtain compound (7); ； f) Compound (7) and Compound (8) are heated to react under alkaline conditions to obtain Compound (9); 。 3. The method for preparing compound (9) according to claim 2, characterized in that: In the preparation steps of compound (8-2): The palladium catalyst ① is selected from palladium acetate or tris(dibenzylideneacetone)dipalladium; the base ① is selected from triethylamine, pyridine or N,N-diisopropylethylamine; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane; the molar ratio of the compound (8-1), 2-ethylhexyl 3-mercaptopropionate and the palladium catalyst ① is 1:1~1.5:0.05~0.1; In the preparation steps of compound (8-3): The anhydrous solvent is anhydrous ethanol; the base ② is potassium tert-butoxide; the molar ratio of the compound (8-2) to the base ② is 1:1-1.5; In the preparation steps of compound (8): The palladium catalyst ② is selected from palladium acetate or tris(dibenzylideneacetone)dipalladium; the base ③ is selected from triethylamine, pyridine or N,N-diisopropylethylamine; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane; the molar ratio of the compound (8-3), the compound (8-4) and the palladium catalyst ② is 1:1~1.5:0.05~0.1; In the preparation steps of compound (7): The acid is selected from hydrochloric acid or trifluoroacetic acid; the reaction solvent is methanol; In the preparation steps of compound (9): The base is potassium carbonate; the molar ratio of the compound (8), the compound (7) and the base is 1:1-1.5:2-5; and the reaction solvent is N-methylpyrrolidone.

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