Preparation method of lisethopram

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a novel method for preparing lisethopran (7-(4, 7-diazaspiro [2.5] octane-7-yl)-2-(2, 8-dimethyl imidazo [1, 2-b] pyridazine-6-yl) pyrido [1, 2-a] pyrimidine-4-ketone). The method comprises the following steps: taking 3-amino-6-pyridazine as an initial raw material, carrying out oxidative carbonylation, bromination, cyclization, Suzuki coupling methylation and Claisen ester condensation reaction in which carbon monoxide is catalyzed by palladium to obtain a key intermediate 3-(2, 8-dimethyl imidazo [1, 2-b] pyridazine-6-yl)-3-oxoethyl propionate, and carrying out reaction on the key intermediate 3-(2, 8-dimethyl imidazo [1, 2-b] pyridazine-6-yl)-3-oxoethyl propionate and 3-(2, 8-dimethyl imidazo [1, 2-b] pyridazine-6-yl)-3-oxoethyl propionate to obtain a target product. The preparation method comprises the following steps: carrying out condensation, Buchwald-Hartwisting reaction and deprotection on 4-(2, 2-b) pyridazine-6-yl)-3-oxoethyl propionate to obtain a final product. The method is high in yield, low in cost, simple and convenient to operate and high in application value.

Description

Technical Field

[0001] The present invention relates to a novel method for preparing lisapram (7-(4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one), and belongs to the field of medicinal chemistry. Background Art

[0002] Lisapram (7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one) is a small molecule drug that targets the SMN2 gene and is jointly developed by Roche, PTCT and the SMA Foundation. It is a new drug for the treatment of spinal muscular atrophy (SMA) and is currently the only small molecule drug used to treat SMA.

[0003] There are currently two reported synthetic routes for 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0004] Route 1: reported by Hasane Ratni et al. in the Journal of Medicinal Chemistry (J MED Chem, 2018, 61, 6501-6517) in 2018, as shown in the figure below:

[0005]

[0006] This route has several major issues: 1. Step a): The starting material, 3,6-dichloro-4-methylpyridazine, has two chlorine atoms in its nucleus, resulting in poor regioselectivity and low yield. 2. Step d): The ring closure is carried out using dimethyl malonate, which consumes a large amount of the raw material and causes excessively high reaction temperatures. 3. Step g): The use of 4,7-diazaspiro[2.5]octane, which contains two reactive sites, as a nucleophile results in poor reaction selectivity and low yield. This reaction route suffers from low yields and significant raw material waste, making it unsuitable for large-scale commercial production.

[0007] Route 2: ADAM, Jean-Michel et al. of Roche optimized the above route in patent WO20190577740 and achieved process scale-up at the tens of grams level, as shown in the figure below:

[0008]

[0009] This route was repeated and the following issues were identified: 1. Step b): The Kumada reaction was cumbersome to perform, as the presence of both bromine and chlorine precluded the use of Suzuki coupling for methylation. 2. Step c): Isopropyl acetate did not react as a reactant, and mechanistically, this reaction was inconceivable. 3. Step d): The Miyaura boronate esterification exhibited poor reactivity and yielded low yields.

[0010] Since the compound 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is very expensive and patient demand is difficult to meet, further design and optimization of its preparation process is extremely meaningful and research-worthy. The present invention aims to provide an alternative reaction route for preparing the compound 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which can avoid the above-mentioned shortcomings of the existing technology methods. The reaction operation and post-processing of this route are simpler, the steps are fewer, the cost is lower, the yield is higher, it meets the requirements of green chemistry, and has the potential for scale-up production. Summary of the Invention

[0011] Based on the problems existing in the route of patent WO20190577740, the purpose of the present invention is to provide a new preparation method of 7-(4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is used to solve the problems of complex reaction operation and low yield of 7-(4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in the above route.

[0012] The objective of the present invention is achieved through the following technical solutions:

[0013] In the present invention, 3-amino-6-pyridazine is used as a starting material, and a key intermediate 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-oxopropionic acid ethyl ester is obtained through palladium-catalyzed carbon monoxide-involved oxidative carbonylation, bromination, ring closure, Suzuki coupling methylation and Claisen ester condensation reaction. The key intermediate 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-oxopropionic acid ethyl ester is condensed with 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-oxopropionic acid ethyl ester, subjected to Buchwald-Hartwig reaction and deprotection to obtain the final product. The eight-step reaction conditions of this route are mild and the post-processing is simple. Compared with patent WO20190577740, it has the following advantages: First, 3-amino-6-chloropyridazine is also used as the starting material, and a palladium-catalyzed oxidative carbonylation reaction involving carbon monoxide is carried out at the beginning of the reaction to convert the chlorine of the pyridazine parent nucleus into an ester group, which is beneficial to improving the selectivity of the subsequent bromination reaction; Second, the methylation strategy adopts the Suzuki coupling reaction strategy, which is simpler to operate than the Kumada reaction adopted in the original route; Third, compared with the original route, the route of the present invention requires fewer reaction steps and has a higher reaction yield.

[0014] The present invention provides a method for preparing a compound of formula I, characterized in that it comprises the following steps:

[0015]

[0016] a) making the compound of formula 1

[0017]

[0018] With carbon monoxide, in the presence of palladium catalyst, phosphine ligand, alkaline reagent and under pressure, react to obtain the compound shown in formula 2

[0019]

[0020] b) subjecting the compound of formula 2 to a bromination reaction in the presence of a brominating agent to obtain a compound of formula 3

[0021]

[0022] c) subjecting the compound of formula 3 to a substitution reaction with 1-bromo-2-acetone to obtain a compound of formula 4

[0023]

[0024] d) subjecting the compound of formula 4 to a Suzuki-Miyaura reaction with methylboronic acid in the presence of a palladium catalyst, a phosphine ligand, and an alkaline reagent to obtain a compound of formula 5

[0025]

[0026] e) subjecting the compound of formula 5 to a Claisen ester condensation reaction with ethyl acetate in the presence of lithium bis(trimethylsilyl)amide to obtain a compound of formula 6

[0027]

[0028] f) subjecting the compound of formula 6 and the compound of formula 7 to a substitution reaction in the presence of a catalyst to obtain a compound of formula 8

[0029]

[0030] g) subjecting the compound of formula 8 and the compound of formula 9 to a substitution reaction in the presence of a palladium catalyst, a phosphine ligand and an alkaline reagent to obtain a compound of formula 10

[0031]

[0032] h) deprotecting the compound of formula 10 to obtain a compound of formula I

[0033] In step a), the reaction conditions and operations may be conventional conditions and operations for such reactions in the art, and the present invention preferably employs the following conditions and operations:

[0034] Furthermore, in step a), the reaction is carried out under protective gas;

[0035] And / or, the palladium catalyst in step a) is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0036] And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0037] And / or, in step a), the alkaline reagent is one or more of diethylamine, triethylamine, ammonia water, diisopropylethylamine, triethylenediamine and pyridine;

[0038] And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.01 to 1:0.1;

[0039] And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1 to 1:1;

[0040] And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2;

[0041] And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1 to 1:2;

[0042] And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1 mmol / mL to 1.5 mmol / mL;

[0043] And / or, in step a), the organic solvent used in the reaction is one or more of an ether solvent and an alcohol solvent;

[0044] And / or, in step a), the reaction pressure is 100 to 200 psi;

[0045] And / or, in step a), the reaction temperature is 0 to 100°C;

[0046] Furthermore, in step a), the reaction is carried out under protective gas;

[0047] And / or, the palladium catalyst in step a) is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0048] And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0049] And / or, in step a), the alkaline reagent is one or more of diethylamine, triethylamine, ammonia water, diisopropylethylamine, triethylenediamine and pyridine;

[0050] And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.01 to 1:0.1;

[0051] And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1 to 1:1;

[0052] And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2;

[0053] And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1 to 1:2;

[0054] And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1 mmol / mL to 1.5 mmol / mL;

[0055] And / or, in step a), the organic solvent used in the reaction is one or more of an ether solvent and an alcohol solvent, the ether solvent is one or more of diethyl ether, dimethyl ether, isopropyl ether, 1,4-dioxane and tetrahydrofuran, and the alcohol solvent is one or more of methanol, ethanol, propanol and isopropanol;

[0056] And / or, in step a), the reaction pressure is 100 to 200 psi;

[0057] And / or, in step a), the reaction temperature is 0-100°C.

[0058] Furthermore, in step a), the protective gas is nitrogen;

[0059] And / or, in step a), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]dichloropalladium, [1,3-bis(diphenylphosphino)propane]dichloropalladium and [1,4-bis(diphenylphosphino)butane]dichloropalladium, preferably palladium chloride;

[0060] And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphinomethane), 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane , 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl) ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, preferably 1,1'-bis(diphenylphosphino)ferrocene;

[0061] And / or, in step a), the alkaline reagent is one or more of diethylamine, triethylamine, ammonia, diisopropylethylamine, triethylenediamine and pyridine, preferably triethylamine;

[0062] And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.01 to 1:0.1, preferably 1:0.1;

[0063] And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1 to 1:1, preferably 1:0.2;

[0064] And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2, preferably 1:2;

[0065] And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1 to 1:2, preferably 1:1;

[0066] And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1 mmol / mL to 1.5 mmol / mL, preferably 1.5 mmol / mL;

[0067] And / or, in step a), the organic solvent used in the reaction is a conventional solvent in the art or for this type of reaction, preferably diethyl ether, dimethyl ether, isopropyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, isopropanol; more preferably ethanol and tetrahydrofuran

[0068] And / or, in step a), the reaction pressure is 150 psi;

[0069] And / or, in step a), the reaction temperature is a conventional temperature for this type of reaction, preferably 0-100°C, more preferably 50-100°C, most preferably 80°C.

[0070] And / or, in step a), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 1 no longer reacts or disappears. The reaction time is preferably 12 to 24 hours, for example, 18 hours.

[0071] And / or, in step a), after the reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: concentrating the reaction solution after the reaction is completed, extracting, washing with water, drying, concentrating and column chromatography. Wherein, the conditions and operations of the extraction are all conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an ester solvent, more preferably ethyl acetate. The conditions and operations of the column chromatography are all conventional conditions and operations in the art. The eluent used for the column chromatography is preferably petroleum ether and ethyl acetate. The volume ratio of the petroleum ether to the ethyl acetate is 100:5 to 100:12.

[0072] In step b), the conditions and operation of the bromination reaction can be the conditions and operation conventional for such reactions in this area, and the present invention preferably uses the following conditions and operation:

[0073] Furthermore, in step b), the bromination reagent used in the bromination reaction is a conventional bromination reagent in the art or in this type of bromination reaction, preferably one or more of liquid bromine, N-bromosuccinimide, and dibromohydantoin;

[0074] And / or, in step b), the organic solvent used in the bromination reaction is a conventional solvent in the art or for this type of bromination reaction, preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane;

[0075] And / or, in step b), the molar ratio of the compound 2 to the brominating reagent is 1:01 to 1:2;

[0076] And / or, in step b), the molar volume ratio of the compound 2 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL;

[0077] And / or, in step b), the temperature of the bromination reaction is a conventional temperature in the art or for this type of bromination reaction, preferably 0 to 100°C.

[0078] Furthermore, in step b), the bromination reagent used in the bromination reaction is a conventional bromination reagent in the art or for this type of bromination reaction, preferably one or more of liquid bromine, N-bromosuccinimide, and dibromohydantoin, most preferably N-bromosuccinimide;

[0079] And / or, in step b), the organic solvent used in the bromination reaction is a conventional solvent in the art or for this type of bromination reaction, preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane, more preferably dimethylformamide and dimethylacetamide, most preferably dimethylformamide;

[0080] And / or, in step b), the molar ratio of the compound 2 to the brominating agent is 1:01 to 1:2, preferably 1:0.26;

[0081] And / or, in step b), the molar volume ratio of the compound 2 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL, preferably 0.05 mmol / mL;

[0082] And / or, in step b), the temperature of the bromination reaction is a conventional temperature in the art or for this type of bromination reaction, preferably 0 to 100°C, more preferably 20 to 50°C, most preferably 30°C.

[0083] And / or, in step b), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 2 no longer reacts or disappears. The reaction time is preferably 4 to 10 hours, for example, 5 hours.

[0084] And / or, in step b), after the reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: concentrating the reaction solution after the reaction is completed, extracting, washing with water, drying, concentrating and column chromatography. Wherein, the conditions and operations of the extraction are conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0085] In step c), the conditions and operations of the substitution reaction may be conventional conditions and operations for such reactions in the art. The present invention preferably uses the following conditions and operations:

[0086] Furthermore, in step c), the molar ratio of the compound 3 to the 1-bromo-2-propanone is 1:0.5 to 1:2;

[0087] And / or, in step c), the organic solvent for the reaction is a conventional solvent in the art or for this type of substitution reaction, preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane; and / or, in step c), the molar ratio of the compound 2 to the organic solvent is 0.1 mmol / mL to 0.5 mmol / mL.

[0088] And / or, in step c), the substitution reaction is carried out at a temperature conventional in the art or for such substitution reactions, preferably at 0 to 100° C.;

[0089] Furthermore, in step c), the molar ratio of the compound 3 to the 1-bromo-2-propanone is 1:0.5 to 1:2, preferably 1:0.8;

[0090] And / or, in step c), the organic solvent for the reaction is a conventional solvent in the art or for this type of substitution reaction, preferably one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane, more preferably methanol or ethanol, most preferably ethanol;

[0091] And / or, in step c), the molar ratio of the compound 2 to the organic solvent is 0.1 mmol / mL to 0.5 mmol / mL, preferably 0.4 mmol / mL;

[0092] And / or, in step c), the substitution reaction is carried out at a temperature conventional in the art or for such substitution reactions, preferably 0 to 100° C., more preferably 50 to 100° C., most preferably 78° C.;

[0093] And / or, in step c), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 3 no longer reacts or disappears. The reaction time is preferably 12 to 24 hours, for example, 16 hours.

[0094] And / or, in step c), after the reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: concentrating the reaction solution after the reaction is completed, extracting, washing with water, drying, concentrating and column chromatography. Wherein, the conditions and operations of the extraction are conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0095] In step d), the conditions and operations of the Suzuki-Miyaura reaction may be conventional conditions and operations for such reactions in the art, and the present invention preferably uses the following conditions and operations:

[0096] Furthermore, in step d), the Suzuki-Miyaura reaction is carried out under protective gas;

[0097] And / or, in step d), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0098] And / or, in step d), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0099] and / or, in step d), the alkaline agent is one or more of alkali metal carbonates, alkali metal phosphates and alkali metal alkoxides;

[0100] And / or, in step d), the molar ratio of the compound 5 to the methylboronic acid is 1:0.1 to 1:2;

[0101] And / or, in step d), the molar ratio of the compound 5 to the palladium catalyst is 10:1 to 20:1;

[0102] And / or, in step d), the molar ratio of the compound 5 to the phosphine ligand is 1:0.01 to 1:0.1;

[0103] And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 2:1;

[0104] And / or, in step d), the molar ratio of the compound 5 to the alkaline reagent is 1:1 to 1:5;

[0105] and / or, in step d), the organic solvent used in the Suzuki-Miyaura reaction is a conventional solvent in the art or this type of Suzuki-Miyaura reaction, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0106] And / or, in step d), the molar volume ratio of the compound 5 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL;

[0107] And / or, in step d), the temperature of the Suzuki-Miyaura reaction is a conventional temperature for such Suzuki-Miyaura reactions in the art, preferably 0 to 100°C.

[0108] Furthermore, in step d), the Suzuki-Miyaura reaction is carried out under protective gas;

[0109] And / or, in step d), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0110] And / or, in step d), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0111] And / or, in step d), the alkaline reagent is one or more of an alkali metal salt, an alkali metal hydroxide, an alkali metal alkoxide and an organic base, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the organic base is one or more of diisopropylethylamine, triethylamine, triethylenediamine and pyridine;

[0112] And / or, in step d), the molar ratio of the compound 5 to the methylboronic acid is 1:0.1 to 1:2;

[0113] And / or, in step d), the molar ratio of the compound 5 to the palladium catalyst is 10:1 to 1:20:1;

[0114] And / or, in step d), the molar ratio of the compound 5 to the phosphine ligand is 1:0.01 to 1:0.1;

[0115] And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 2:1;

[0116] And / or, in step d), the molar ratio of the compound 5 to the alkaline reagent is 1:1 to 1:5;

[0117] and / or, in step d), the organic solvent used in the Suzuki-Miyaura reaction is a conventional solvent in the art or this type of Suzuki-Miyaura reaction, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0118] And / or, in step d), the molar volume ratio of the compound 5 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL;

[0119] And / or, in step d), the temperature of the Suzuki-Miyaura reaction is a conventional temperature for such Suzuki-Miyaura reactions in the art, preferably 0 to 100°C.

[0120] Furthermore, in step d), the protective gas is argon;

[0121] And / or, in step d), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]dichloropalladium, [1,3-bis(diphenylphosphino)propane]dichloropalladium and [1,4-bis(diphenylphosphino)butane]dichloropalladium, preferably palladium chloride;

[0122] And / or, in step d), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphinomethane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1, One or more of 6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, preferably 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene;

[0123] And / or, in step d), the alkaline reagent is one or more of an alkali metal salt, an alkali metal hydroxide, an alkali metal alkoxide and an organic base, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, the organic base is one or more of diisopropylethylamine, triethylamine, triethylenediamine and pyridine, more preferably an alkali metal phosphate, most preferably potassium phosphate;

[0124] And / or, in step d), the molar ratio of the compound 5 to the methylboronic acid is 1:0.1 to 1:2, preferably 1:0.66;

[0125] And / or, in step d), the molar ratio of the compound 5 to the palladium catalyst is 10:1 to 1:20:1, preferably 20:1;

[0126] And / or, in step d), the molar ratio of the compound 5 to the phosphine ligand is 1:0.01 to 1:0.1, preferably 1:0.01;

[0127] And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 2:1, preferably 1:1;

[0128] And / or, in step d), the molar ratio of the compound 5 to the alkaline reagent is 1:1 to 1:5, preferably 1:3;

[0129] and / or, in step d), the organic solvent used in the Suzuki-Miyaura reaction is a conventional solvent in the art or this type of Suzuki-Miyaura reaction, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane, preferably cyclopentyl methyl ether;

[0130] And / or, in step d), the molar volume ratio of the compound 5 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL, preferably 0.33 mmol / mL;

[0131] And / or, in step d), the temperature of the Suzuki-Miyaura reaction is a conventional temperature for such Suzuki-Miyaura reactions in the art, preferably 0-100°C, more preferably 50-100°C, and most preferably 80°C.

[0132] And / or, in step d), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 4 no longer reacts or disappears. The reaction time is preferably 10 to 24 hours, for example, 16 hours.

[0133] And / or, in step d), after the reduction reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: concentrating the reaction solution after the reaction is completed, extracting, washing with water, drying, concentrating and column chromatography. Wherein, the conditions and operations of the extraction are conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0134] In step e), the conditions and operation of the Claisen ester condensation reaction can be the conditions and operations conventional for such reactions in the art, and the present invention preferably uses the following conditions and operations:

[0135] Furthermore, in step e), the Claisen ester condensation reaction is carried out under protective gas;

[0136] And / or, in step e), the molar ratio of the compound 5 to the ethyl acetate is 1:1 to 1:5;

[0137] And / or, in step e), the molar ratio of the compound 5 to the lithium bistrimethylsilylamide is 1:1 to 1:5;

[0138] and / or, in step e), the organic solvent used in the Claisen ester condensation reaction is a conventional solvent in the art or for such Claisen ester condensation reactions, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0139] and / or, in step e), the molar ratio of the compound 5 to the organic solvent is 0.1 mmol / mL to 1 mmol / mL;

[0140] and / or, in step e), the temperature of the Claisen ester condensation reaction is a conventional temperature for such Claisen ester condensation reactions in the art, preferably -78 to 0° C.;

[0141] Furthermore, in step e), the protective gas is argon;

[0142] And / or, in step e), the molar ratio of the compound 5 to the ethyl acetate is 1:1 to 1:5, preferably 1:4;

[0143] And / or, in step e), the molar ratio of the compound 5 to the lithium bis(trimethylsilyl)amide is 1:1 to 1:5, preferably 1:2

[0144] and / or, in step e), the organic solvent used in the Claisen ester condensation reaction is a conventional solvent in the art or for such Claisen ester condensation reactions, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane, more preferably tetrahydrofuran;

[0145] And / or, in step e), the molar ratio of the compound 5 to the organic solvent is 0.1 mmol / mL to 1 mmol / mL, more preferably 0.56 mmol / mL.

[0146] And / or, in step e), the temperature of the Claisen ester condensation reaction is a conventional temperature for such Claisen ester condensation reactions in the art, preferably -78 to 0° C., more preferably -50 to -20° C., and most preferably -40° C.;

[0147] And / or, in step e), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 5 no longer reacts or disappears. The reaction time is preferably 1 to 5 hours, for example, 2 hours.

[0148] And / or, in step e), after the Claisen ester condensation reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: quenching the reaction solution after the reaction is completed, concentrating, extracting, washing with water, drying, concentrating and column chromatography. Among them, the conditions and operations of the quenching are all conventional conditions and operations in the field. The quenching agent used in the quenching operation is preferably water. The conditions and operations of the extraction are all conventional conditions and operations in the field. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0149] In step f), the conditions and operations of the substitution reaction may be conventional conditions and operations for such reactions in the art. The present invention preferably uses the following conditions and operations:

[0150] Furthermore, in step f), the catalyst is one or more of cuprous bromide, polyphosphoric acid, p-toluenesulfonic acid, bismuth trichloride, bismuth trifluoromethanesulfonate, indium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, and zinc difluoromethanesulfonate;

[0151] And / or, in step f), the molar ratio of compound 6 to compound 7 is 1:1 to 1:2;

[0152] And / or, in step f), the molar ratio of the compound 6 to the catalyst is 10:1 to 5:1;

[0153] And / or, in step f), the organic solvent used in the substitution reaction is a conventional solvent in the art or for this type of substitution reaction, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0154] And / or, in step f), the molar volume ratio of the compound 6 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL;

[0155] And / or, in step f), the temperature of the substitution reaction is a conventional temperature in the art or for this type of substitution reaction, preferably 0 to 150°C.

[0156] Furthermore, in step f), the catalyst is indium trifluoromethanesulfonate;

[0157] And / or, in step f), the molar ratio of compound 6 to compound 7 is 1:1 to 1:2, preferably 1:1.2;

[0158] And / or, in step f), the molar ratio of the compound 6 to the catalyst is 10:1 to 5:1, preferably 5:1;

[0159] And / or, in step f), the organic solvent used in the substitution reaction is a conventional solvent in the art or for such substitution reactions, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane, preferably toluene;

[0160] And / or, in step f), the molar volume ratio of the compound 6 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL, preferably 0.6 mmol / mL;

[0161] And / or, in step f), the temperature of the substitution reaction is a conventional temperature in the art or for such substitution reactions, preferably 0 to 150° C., preferably 100 to 120° C., and optimally 105° C.;

[0162] And / or, in step f), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 6 no longer reacts or disappears. The reaction time is preferably 1 to 18 hours, for example, 12 hours.

[0163] And / or, in step f), after the substitution reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: quenching the reaction solution after the reaction is completed, concentrating, extracting, washing with water, drying, concentrating and column chromatography. Among them, the conditions and operations of the quenching are all conventional conditions and operations in the field. The quenching reagent used in the quenching operation is preferably water. The conditions and operations of the extraction are all conventional conditions and operations in the field. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0164] In step g), the conditions and operations of the substitution reaction may be conventional conditions and operations for such reactions in the art. The present invention preferably uses the following conditions and operations:

[0165] Further, in step g), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0166] And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0167] and / or, in step g), the alkaline agent is one or more of alkali metal carbonates, alkali metal phosphates and alkali metal alkoxides;

[0168] And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 5:1 to 20:1;

[0169] And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 5:1 to 20:1;

[0170] And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2;

[0171] And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:1 to 1:5;

[0172] And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1 to 1:2;

[0173] And / or, in step g), the organic solvent used in the substitution reaction is a conventional solvent in the art or for such substitution reactions, preferably N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0174] And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.1 mmol / mL to 0.5 mmoL / mL;

[0175] And / or, in step g), the temperature of the substitution reaction is a conventional temperature in the art or for such substitution reactions, preferably 0 to 100° C.;

[0176] Further, in step g), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride;

[0177] And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0178] And / or, in step g), the alkaline agent is one or more of an alkali metal salt, an alkali metal hydroxide and an alkali metal alkoxide, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, and the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide;

[0179] And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 5:1 to 20:1;

[0180] And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 5:1 to 20:1;

[0181] And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2;

[0182] And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:1 to 1:5;

[0183] And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1 to 1:2;

[0184] And / or, in step g), the organic solvent used in the substitution reaction is a conventional solvent in the art or for such substitution reactions, preferably N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane;

[0185] And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.1 mmol / mL to 0.5 mmoL / mL;

[0186] And / or, in step g), the temperature of the substitution reaction is a conventional temperature in the art or for this type of substitution reaction, preferably 0 to 100°C.

[0187] Further, in step g), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]dichloropalladium, [1,3-bis(diphenylphosphino)propane]dichloropalladium and [1,4-bis(diphenylphosphino)butane]dichloropalladium, preferably palladium acetate;

[0188] And / or, in step g), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphinomethane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1, One or more of 6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, preferably 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene;

[0189] And / or, in step g), the alkaline agent is one or more of an alkali metal salt, an alkali metal hydroxide and an alkali metal alkoxide, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, and the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, more preferably an alkali metal alkoxide, and most preferably sodium tert-butoxide;

[0190] And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 5:1 to 20:1, preferably 20:1;

[0191] And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 5:1 to 20:1, preferably 10:1;

[0192] And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2, preferably 1:2;

[0193] And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:1 to 1:5, preferably 1:3;

[0194] And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1 to 1:2, preferably 1:1.1;

[0195] And / or, in step g), the organic solvent used in the substitution reaction is a conventional solvent in the art or for such substitution reactions, preferably N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane, more preferably tetrahydrofuran;

[0196] And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.1 mmol / mL to 0.5 mmol / mL, preferably 0.18 mmol / mL;

[0197] And / or, in step g), the temperature of the substitution reaction is a conventional temperature in the art or for this type of substitution reaction, preferably 0-100°C, more preferably 10-50°C, and most preferably 30°C.

[0198] And / or, in step g), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 8 no longer reacts or disappears. The reaction time is preferably 1 to 12 hours, for example, 6 hours.

[0199] And / or, in step g), after the substitution reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: concentrating the reaction solution after the reaction is completed, extracting, washing with water, drying, concentrating and column chromatography. Wherein, the conditions and operations of the extraction are all conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an ester solvent, more preferably ethyl acetate. The conditions and operations of the column chromatography are all conventional conditions and operations in the art. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10.

[0200] In step h), the conditions and operations for the deprotection reaction may be conventional conditions and operations for such reactions in the art.

[0201] The present invention preferably adopts the following conditions and operations:

[0202] Furthermore, in step h), the deprotection reaction is carried out under protective gas;

[0203] And / or, in step h), the removal reagent used for the deprotection group is one of sodium hydrosulfide, sodium sulfide, sodium ethanethiolate, thiophenol, sodium p-toluenethiophenol, potassium fluoride, lithium tri-sec-butylborohydride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethylsilyl iodide, cerium trichloride, ammonium cerium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and hydrochloric acid;

[0204] And / or, in step h), the molar ratio of the compound 10 to the removal reagent used for the deprotection group is 1:1 to 1:8;

[0205] and / or, in step h), the organic solvent used in the deprotection reaction is a conventional solvent for such deprotection reactions in the art, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, nitrogen-methylpyrrolidone, methanol, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate, propyl acetate and acetic acid; and / or, in step h), the molar volume ratio of compound 10 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL;

[0206] And / or, in step h), the temperature of the deprotection reaction is a conventional temperature in the art or for this type of deprotection reaction, preferably 0 to 110°C.

[0207] Furthermore, in step h), the protective gas is argon;

[0208] And / or, in step h), the removal reagent used for the deprotection group is one of sodium hydrosulfide, sodium sulfide, sodium ethanethiolate, thiophenol, sodium p-toluenethiophenol, potassium fluoride, lithium tri-sec-butylborohydride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethylsilyl iodide, cerium trichloride, ammonium cerium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and hydrochloric acid, preferably hydrochloric acid;

[0209] And / or, in step h), the molar ratio of the compound 10 to the hydrochloric acid is 1:1 to 1:8, preferably 1:2;

[0210] And / or, in step h), the organic solvent used in the deprotection reaction is a conventional solvent for such deprotection reactions in the art, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, nitrogen methyl pyrrolidone, methanol, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate, propyl acetate and acetic acid,

[0211] More preferably, propyl acetate;

[0212] and / or, the molar volume ratio of the compound 10 to the organic solvent in step h) is 0.05 mmol / mL to 1 mmol / mL, preferably 0.05 mmol / mL;

[0213] And / or, in step h), the temperature of the deprotection reaction is a conventional temperature in the art or for this type of deprotection reaction, preferably 0-110°C, more preferably 50-80°C, and most preferably 75°C.

[0214] And / or, in step h), and / or, in step h), the progress of the reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), and the reaction endpoint is generally determined as the end point when compound 10 no longer reacts or disappears. The reaction time is preferably 1 to 12 hours, for example, 6 hours.

[0215] And / or, in step h), after the reduction reaction is completed, post-treatment may be further included. The post-treatment includes the following steps: quenching the reaction solution after the reaction is completed, concentrating, extracting, washing with water, drying, concentrating, and column chromatography. Among them, the conditions and operations of the quenching are all conventional conditions and operations in the art. The quenching reagent used in the quenching operation is preferably hydrochloric acid. Among them, the conditions and operations of the extraction are all conventional conditions and operations in the art. The organic solvent used for the extraction is preferably an alkane solvent, more preferably dichloromethane. The conditions and operations of the column chromatography are all conventional conditions and operations in the art. The eluent used for the column chromatography is preferably dichloromethane and methanol. The volume ratio of the dichloromethane to the methanol is 100:1 to 100:10. DETAILED DESCRIPTION

[0216] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0217] Example 1

[0218] Step a)

[0219] Synthesis of 6-aminopyridazine-3-carboxylic acid ethyl ester

[0220]

[0221] Under nitrogen bubbling pressure, to a solution of 3-amino-6-chloropyridazine (3.00 g, 23.16 mmol) in 15 mL of EtOH / THF (1:1) in a steel reactor, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (1.695 g, 2.32 mmol) and Et3N (2.812 g, 27.79 mmol) were stirred. The resulting reaction mixture was stirred at 80°C under a carbon monoxide atmosphere (150 psi) for 18 h. After completion, the ethanol solvent was removed by spin drying, 10 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 x 20 mL). The organic phases were combined and washed twice with saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. An appropriate amount of 160-200 mesh silica gel was added and the sample was separated and purified by column chromatography to obtain 3.031 g of a white solid in a yield of 78.3%.

[0222] 1 H NMR (400MHz, CD3OD) δ7.88 (d, J = 9.3 Hz, 1H), 6.94 (d, J = 9.3 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). HRMS(ESI):m / z calcd forC7H 10 N3O2(M+H) + 168.0768,found(M+H) + 168.0765.

[0223] Step b)

[0224] Synthesis of 5-bromo-6-aminopyridazine-3-carboxylic acid ethyl ester

[0225]

[0226] In a 10 mL round-bottom flask, ethyl 6-aminopyridazine-3-carboxylate (500 mg, 2 mmol) was dissolved in 40 mL of DMF. Sodium acetate (383 mg, 4.67 mmol) and acetic acid (97 mL, 1.62 mmol) were added, and N-bromosuccinimide (1.277 g, 7.18 mmol) was added in three batches. The mixture was stirred at 30°C for several hours. After completion of the reaction, the methanol solvent was dried, and 4 mL of saturated aqueous sodium sulfite solution was added to quench the reaction. 10 mL of water was added, and the pH of the aqueous phase was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The mixture was then extracted three times with dichloromethane (3 × 20 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate and concentrated.

[0227] 1H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 6.32 (s, 2H), 4.48 (q, J = 7.0Hz, 2H), 1.43 (t, J = 7.1Hz, 3H). MS (ESI): m / z calcd forC7H9BrN3O2 (M+H) + 502.2561,found(M+H) + 502.2558.

[0228] Step c)

[0229] Synthesis of 8-bromo-2-methylimidazo[1,2-b]pyridazine-6-carboxylic acid ethyl ester

[0230]

[0231] In a 10 mL round-bottom flask, ethyl 5-bromo-6-aminopyridazine-3-carboxylate (50 mg, 0.20 mmol) was dissolved in 0.5 mL of ethanol. Bromoacetone (34 mg, 0.25 mmol) was added and stirred at 78°C for several hours. After completion of the reaction, the ethanol solvent was dried, 2 mL of water was added, and the pH of the aqueous phase was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted three times with dichloromethane (3 x 4 mL). The organic phases were combined and washed with saturated sodium chloride solution. An appropriate amount of anhydrous sodium sulfate was added to the washed organic phases, dried, and concentrated. An appropriate amount of 160-200 mesh silica gel was added and the sample was separated and purified by column chromatography to obtain 48 mg of a white solid in an 83.1% yield.

[0232] 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.95 (s, 1H), 4.52 (q, J = 7.1Hz, 2H), 2.57 (s, 3H), 1.46 (t, J = 7.2Hz, 3H). MS (ESI): m / z calcd for C 10 H 11 BrN3O2(M+H) + 284.0037,285.9996,found(M+H) + 284.0032,285.9991.

[0233] Step d)

[0234] Synthesis of ethyl 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylate

[0235]

[0236] Under argon atmosphere, in a 10 mL thick-walled pressure bottle, ethyl 8-bromo-2-methylimidazo[1,2-b]pyridazine-6-carboxylate (135 mg, 0.48 mmol) was dissolved in 1.5 mL of deoxygenated cyclopentyl methyl ether, and 0.5 mL of deoxygenated water was added. Methylboric acid (43 mg, 0.72 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene)palladium dichloride (19 mg, 5.0 mol%), and potassium phosphate (195 mg, 1.43 mmol) were then added. The mixture was stirred at 80°C for 16 h. After completion of the reaction, 5 mL of water was added, and the mixture was extracted three times with dichloromethane (3 × 10 mL). The organic phases were combined and washed twice with saturated aqueous sodium chloride solution. Anhydrous sodium sulfate was added to the washed organic phases for drying. An appropriate amount of 160-200 mesh silica gel was added and the sample was stirred. After column chromatography, 84 mg of a yellow-green solid was obtained with a yield of 80.4%.

[0237] 1 H NMR (400MHz, CDCl3) δ7.84(s,1H),7.52(s,1H),4.49(q,J=7.2Hz,2H),2.68(s,3H),2.52(s,3H),1.44(t,J=7.2Hz,3H).MS(ESI):m / z calcd forC 11 H 14 N3O2(M+H) + 220.1081,found(M+H) + 220.1077.

[0238] Step e)

[0239] Synthesis of ethyl 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-oxopropanoate

[0240]

[0241] Under argon atmosphere, in a 25 mL three-necked flask, ethyl 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylate (500 mg, 2.82 mmol) was dissolved in 5 mL of ultra-dry tetrahydrofuran. Anhydrous ethyl acetate (1.01 g, 11.41 mmol) was added, followed by the slow dropwise addition of lithium bis(trimethylsilyl)amide (1 M, 5.71 mL, 5.71 mmol). The reaction was stirred at -40°C for 2 h. After completion, the reaction was quenched by the addition of 10 mL of water and extracted three times with dichloromethane (3 × 20 mL). The organic phases were combined and washed twice with saturated sodium chloride solution. An appropriate amount of anhydrous sodium sulfate was added to the washed organic phases for drying. An appropriate amount of 160-200 mesh silica gel was added and the sample was separated and purified by column chromatography to obtain 523 mg of a yellow-green solid in an 87.8% yield.

[0242] 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 7.52 (s, 1H), 4.20 (q, J = 7.1Hz, 2H), 4.14 (s, 2H), 2.69 (s, 3H), 2.54 (s, 3H), 1.24 (t, J = 7.2Hz, 3H). HRMS (ESI): m / z calcd forC 13 H 16 N3O3(M+H) + 262.1186,found(M+H) + 262.1182.

[0243] Step f)

[0244] Synthesis of 7-bromo-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

[0245]

[0246] In a round-bottom flask, 2-amino-5-bromopyridine (200 mg, 1.16 mmol) and ethyl 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-oxopropanoate (366 mg, 1.04 mmol) were dissolved in 2 mL of toluene. Indium trifluoromethanesulfonate (131 mg, 0.23 mmol) was added and stirred at 100°C for several hours. After completion, the reaction was quenched by adding 10 mL of water and extracted three times with dichloromethane (3 × 20 mL). The organic phases were combined and washed twice with saturated sodium chloride solution. An appropriate amount of anhydrous sodium sulfate was added to the washed organic phases for drying. An appropriate amount of 160-200 mesh silica gel was added and the sample was separated and purified by column chromatography to obtain 287 mg of a light yellow solid in a yield of 66.69%.

[0247] 1 H NMR(400MHz, CDCl3)δ9.23(d,J=2.2Hz,1H),7.94(s,1H),7.83(dd,J=9.4,2.2Hz,1H),7 .80(s,1H),7.65(d,J=9.4Hz,1H),7.45(s,1H),2.75(s,3H),2.56(s,3H).MS(ESI):m / z calcd for C 16 H 13 BrN5O(M+H) + 370.0292,found(M+H) + 370.0296, 372.0257.

[0248] Step g)

[0249] Synthesis of tert-butyl 7-(2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0250]

[0251] Under argon atmosphere, in a 10 mL round-bottom flask, 7-bromo-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (68 mg, 0.18 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (44 mg, 0.20 mmol) were dissolved in 1 mL of THF, and palladium acetate (2 mg, 4.8 mmol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg, 9.6 mmol%) and NaOtBu (52 mg, 0.53 mmol) were added, and the reaction was stirred at 40 ° C for several hours. After the reaction was completed, 2 mL of water was added, and the mixture was extracted three times with dichloromethane (3×5 mL). The organic phases were combined and washed twice with a saturated aqueous sodium chloride solution. An appropriate amount of anhydrous sodium sulfate was added to the washed organic phase for drying. An appropriate amount of 160-200 mesh silica gel was added and the sample was mixed. After column chromatography separation and purification, 58.5 mg of a yellow-green solid was obtained with a yield of 63.3%.

[0252] 1 H NMR (500MHz, CDCl3) δ8.42(d,J=2.7Hz,1H),7.95(s,1H),7.79(d,J=0.9Hz,1H),7.73-7.66(m,2H),7.36(s,1H),3.76(t,J=5.1Hz, 2H),3.27(t,J=5.2Hz,2H),3.06(s,2H),2.75(s,3H),2.55(s,3H),1.48(s,9H),1.13-1.08(m,2H),0.91-0.86(m,2H).MS(ESI):m / z calcd for C 27 H 32 N7O3(M+H) + 502.2561,found(M+H) + 502.2558.

[0253] Step h)

[0254] Synthesis of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one

[0255]

[0256] In a 10 mL round-bottom flask, tert-butyl 7-(2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (50 mg, 0.10 mmol) was dissolved in 2 mL of propyl acetate. 0.32 mL of 4 M HCl in 1,4-dioxane (0.8 mmol) was added and stirred at 75°C for several hours. After completion of the reaction, 2 mL of water was added, and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was extracted three times with dichloromethane (3 × 5 mL). The organic phases were combined and washed twice with saturated sodium chloride. Anhydrous sodium sulfate was added to the washed organic phases for drying. An appropriate amount of 160-200 mesh silica gel was added and the sample was stirred. After column chromatography, 38 mg of a yellow-green solid was obtained in a 95% yield.

[0257] 1 H NMR(500MHz, CDCl3)δ8.4(d,J=2.7Hz,1H),7.88(s,1H),7.76(s,1H),7.71-7.64(m,2H),7.33(s,1H),3.26-3.19(m,2H),3 .19-3.13(m,2H),3.05(s,2H),2.70(s,3H),2.51(s,3H),1.91(s,1H),0.76-0.70(m,2H),0.65-0.60(m,2H).MS(ESI):m / z calcd forC 22 H 24 N7O(M+H) + 402.2039,found(M+H) + 402.2037.

Claims

1. A method for preparing a compound of formula I, characterized in that: The following steps are involved: a) making the compound of formula 1 With carbon monoxide, in the presence of palladium catalyst, phosphine ligand, alkaline reagent and under pressure, react to obtain the compound shown in formula 2 b) subjecting the compound of formula 2 to a bromination reaction in the presence of a brominating agent to obtain a compound of formula 3 c) subjecting the compound of formula 3 to a substitution reaction with 1-bromo-2-acetone to obtain a compound of formula 4 d) reacting the compound of formula 4 with methylboronic acid in the presence of a palladium catalyst, a phosphine ligand and an alkaline reagent to obtain a compound of formula 5 e) subjecting the compound of formula 5 to a Claisen ester condensation reaction with ethyl acetate in the presence of lithium bis(trimethylsilyl)amide to obtain a compound of formula 6 f) subjecting the compound of formula 6 and the compound of formula 7 to a substitution reaction in the presence of a catalyst to obtain a compound of formula 8 g) subjecting the compound of formula 8 and the compound of formula 9 to a substitution reaction in the presence of a palladium catalyst, a phosphine ligand and an alkaline reagent to obtain a compound of formula 10 h) deprotecting the compound of formula 10 to obtain the compound of formula I.

2. The preparation method according to claim 1, characterized in that In step a), the reaction is carried out under protective gas; And / or, the palladium catalyst in step a) is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; And / or, in step a), the alkaline reagent is one or more of diethylamine, triethylamine, ammonia water, diisopropylethylamine, triethylenediamine and pyridine; And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.01 to 1:0.1; And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1 to 1:1; And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2; And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1 to 1:2; And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1 mmol / mL to 1.5 mmol / mL; And / or, in step a), the organic solvent used in the reaction is one or more of an ether solvent and an alcohol solvent; And / or, in step a), the reaction pressure is 100 to 200 psi; And / or, in step a), the reaction temperature is 0-100°C.

3. The preparation method according to claim 2, characterized in that In step a), the reaction is carried out under protective gas; And / or, the palladium catalyst in step a) is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step a), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; And / or, in step a), the alkaline reagent is one or more of diethylamine, triethylamine, ammonia water, diisopropylethylamine, triethylenediamine and pyridine; And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.01 to 1:0.1; And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1 to 1:1; And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2; And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1 to 1:2; And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1 mmol / mL to 1.5 mmol / mL; And / or, in step a), the organic solvent used in the reaction is one or more of an ether solvent and an alcohol solvent, the ether solvent is one or more of diethyl ether, dimethyl ether, isopropyl ether, 1,4-dioxane and tetrahydrofuran, and the alcohol solvent is one or more of methanol, ethanol, propanol and isopropanol; And / or, in step a), the reaction pressure is 100 to 200 psi; And / or, in step a), the reaction temperature is 0-100°C.

4. The preparation method according to claim 3, characterized in that In step a), the protective gas is nitrogen; And / or, in step a), the palladium catalyst is palladium chloride; and / or, in step a), the phosphine ligand is 1,1'-bis(diphenylphosphino)ferrocene; And / or, in step a), the alkaline reagent is triethylamine; And / or, in step a), the molar ratio of the compound 1 to the palladium catalyst is 1:0.1; And / or, in step a), the molar ratio of the compound 1 to the phosphine ligand is 1:0.2; And / or, in step a), the molar ratio of the palladium catalyst to the phosphine ligand is 1:2; And / or, in step a), the molar ratio of the compound 1 to the alkaline reagent is 1:1; And / or, in step a), the molar volume ratio of the compound 1 to the organic solvent is 1.5 mmol / mL; And / or, in step a), the organic solvent used in the reaction is ethanol and tetrahydrofuran; And / or, in step a), the reaction pressure is 150 psi; And / or, in step a), the reaction temperature is 80°C.

5. The preparation method according to claim 1, characterized in that In step b), the bromination reagent is one or more of liquid bromine, N-bromosuccinimide, and dibromohydantoin; And / or, in step b), the organic solvent for the reaction is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane; And / or, in step b), the molar ratio of the compound 2 to the brominating reagent is 1:0.1 to 1:2; And / or, in step b), the molar volume ratio of the compound 2 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL; And / or, in step b), the reaction temperature is 0-100°C.

6. The preparation method according to claim 5, characterized in that In step b), the bromination reagent N-bromosuccinimide; And / or, in step b), the organic solvent for the reaction is dimethylformamide; And / or, in step b), the molar ratio of the compound 2 to the brominating reagent is 1:0.26; And / or, in step b), the molar volume ratio of the compound 2 to the organic solvent is 0.05 mmol / mL; And / or, in step b), the reaction temperature is 30°C.

7. The preparation method according to claim 1, characterized in that In step c), the compound 3 and the 1- The molar ratio of bromo-2-propanone is 1:0.5 to 1:2; and / or, in step c), the organic solvent for the reaction is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, and dichloromethane; And / or, in step c), the molar ratio of the compound 2 to the organic solvent is 0.1 mmol / mL to 0.5 mmol / mL. And / or, in step c), the reaction temperature is 0-100°C.

8. The preparation method according to claim 7, characterized in that In step c), the molar ratio of the compound 3 to the 1-bromo-2-propanone is 1:0.8; And / or, in step c), the organic solvent for the reaction is ethanol; And / or, in step c), the molar ratio of the compound 2 to the organic solvent is 0.4 mmol / mL And / or, in step c), the reaction temperature is 78°C.

9. The preparation method according to claim 1, characterized in that In step d), the Suzuki-Miyaura reaction is carried out under protective gas; And / or, in step d), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step d), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; and / or, in step d), the alkaline agent is one or more of alkali metal carbonates, alkali metal phosphates and alkali metal alkoxides; And / or, in step d), the molar ratio of the compound 4 to the methylboronic acid is 1:0.1 to 1:2; And / or, in step d), the molar ratio of the compound 4 to the palladium catalyst is 10:1 to 20:1; And / or, in step d), the molar ratio of the compound 4 to the phosphine ligand is 1:0.01 to 1:0.1; And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 2:1; And / or, in step d), the molar ratio of the compound 4 to the alkaline reagent is 1:1 to 1:5; and / or, in step d), the organic solvent used in the reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step d), the molar volume ratio of the compound 5 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL; And / or, in step d), the reaction temperature is 0-100°C.

10. The preparation method according to claim 9, characterized in that In step d), the Suzuki-Miyaura reaction is carried out under protective gas; And / or, in step d), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step d), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; And / or, in step d), the alkaline reagent is one or more of an alkali metal salt, an alkali metal hydroxide, an alkali metal alkoxide and an organic base, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the organic base is one or more of diisopropylethylamine, triethylamine, triethylenediamine and pyridine; And / or, in step d), the molar ratio of the compound 4 to the methylboronic acid is 1:0.1 to 1:2; And / or, in step d), the molar ratio of the compound 4 to the palladium catalyst is 10:1 to 1:20:1; And / or, in step d), the molar ratio of the compound 4 to the phosphine ligand is 1:0.01 to 1:0.1; And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2; And / or, in step d), the molar ratio of the compound 4 to the alkaline reagent is 1:1 to 1:5; and / or, in step d), the organic solvent used in the reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step d), the molar volume ratio of the compound 4 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL; And / or, in step d), the reaction temperature is 0-100°C.

11. The preparation method according to claim 10, characterized in that: In step d), the protective gas is argon; And / or, in step d), the palladium catalyst is palladium chloride; And / or, in step d), the phosphine ligand is 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene; And / or, in step d), the alkaline reagent is potassium phosphate; And / or, in step d), the molar ratio of the compound 4 to the methylboric acid is 1:0.66; And / or, in step d), the molar ratio of the compound 4 to the palladium catalyst is 20:1; And / or, in step d), the molar ratio of the compound 4 to the phosphine ligand is 1:0.05; And / or, in step d), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1; And / or, in step d), the molar ratio of the compound 4 to the alkaline reagent is 1:3; And / or, in step d), the organic solvent used in the reaction is cyclopentyl methyl ether; And / or, in step d), the molar volume ratio of the compound 4 to the organic solvent is 0.33 mmol / mL; And / or, in step d), the reaction temperature is 80°C.

12. The preparation method according to claim 1, characterized in that In step e), the Claisen ester condensation reaction is carried out under protective gas; And / or, in step e), the molar ratio of the compound 5 to the ethyl acetate is 1:1 to 1:5; And / or, in step e), the molar ratio of the compound 5 to the lithium bis(trimethylsilyl)amide is 1:1 to 1:5 And / or, in step e), the organic solvent for the reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step e), the molar ratio of the compound 5 to the organic solvent is 0.1 mmol / mL to 1 mmol / mL. And / or, in step e), the reaction temperature is -78 to 0°C.

13. The preparation method according to claim 12, characterized in that In step e), the protective gas is argon; And / or, in step e), the molar ratio of the compound 5 to the ethyl acetate is 1:4; And / or, in step e), the molar ratio of the compound 5 to the lithium bis(trimethylsilyl)amide is 1:2 And / or, in step e), the organic solvent for the reaction is tetrahydrofuran; And / or, in step e), the molar ratio of the compound 5 to the organic solvent is 0.56 mmol / mL. And / or, in step e), the reaction temperature is -40°C.

14. The preparation method according to claim 1, characterized in that In step f), the catalyst is one or more of cuprous bromide, polyphosphoric acid, p-toluenesulfonic acid, bismuth trichloride, bismuth trifluoromethanesulfonate, indium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, and zinc difluoromethanesulfonate; And / or, in step f), the molar ratio of compound 6 to compound 7 is 1:1 to 1:2; And / or, in step f), the molar ratio of the compound 6 to the catalyst is 10:1 to 5:1; And / or, in step f), the organic solvent used in the reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step f), the molar volume ratio of the compound 6 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL; And / or, in step f), the reaction temperature is 0-150°C.

15. The preparation method according to claim 14, characterized in that In step f), the catalyst is indium trifluoromethanesulfonate; And / or, in step f), the molar ratio of compound 6 to compound 7 is 1:1.2; And / or, in step f), the molar ratio of the compound 6 to the catalyst is 5:1; And / or, in step f), the organic solvent used in the reaction is toluene; And / or, in step f), the molar volume ratio of the compound 6 to the organic solvent is 0.6 mmol / mL; And / or, in step f), the reaction temperature is 105°C.

16. The preparation method according to claim 1, characterized in that In step g), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step g), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; and / or, in step g), the alkaline agent is one or more of alkali metal carbonates, alkali metal phosphates and alkali metal alkoxides; And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 5:1 to 20:1; And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 5:1 to 20:1; And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2; And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:1 to 1:5; And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1 to 1:2; And / or, in step g), the organic solvent used in the reaction is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.1 mmol / mL to 0.5 mmoL / mL; And / or, in step g), the reaction temperature is 0-100°C.

17. The preparation method according to claim 16, characterized in that In step g), the palladium catalyst is one or more of palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, palladium acetylacetonate, palladium hydroxide, palladium trifluoroacetate, palladium nitrate, palladium sulfate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, dichlorobistriphenylphosphine palladium and dichlorodibenzonitrile palladium, bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium, (bis(di-tert-butylphenylphosphine)palladium(II) dichloride), [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride and [1,4-bis(diphenylphosphino)butane]palladium dichloride; And / or, in step g), the phosphine ligand is tri(2-methoxyphenyl)phosphine, triphenylphosphine, tri(4-methyl-phenyl)phosphine, tri(4-methoxy-phenyl)phosphine, tri(3-methoxy-phenyl)phosphine, tri(2,6-dimethoxy-phenyl)phosphine, tri(2,4,6-trimethoxy-phenyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, benzyldiphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4 - one or more of bis(diphenylphosphino)butane, 1,6-bis(diphenylphosphino)hexane, 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 4,6-bis(diphenylphosphino)phenazine, 3-(dicyclohexylphosphino)-1-methyl-2-phenyl-1H-indole, bis(2-diphenylphosphinophenyl)ether, 1,2-bis(diphenylphosphino)benzene, 1,1'-bis(diphenylphosphino)ferrocene, and R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; And / or, in step g), the alkaline agent is one or more of an alkali metal salt, an alkali metal hydroxide and an alkali metal alkoxide, the alkali metal salt is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate, the alkali metal hydroxide is one or more of sodium hydroxide and calcium hydroxide, and the alkali metal alkoxide is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 5:1 to 20:1; And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 5:1 to 20:1; And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:1 to 1:2; And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:1 to 1:5; And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1 to 1:2; And / or, in step g), the organic solvent used in the reaction is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, acetone, carbon tetrachloride, petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, chlorobenzene, xylene, trimethylbenzene, trifluorotoluene, anisole, dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.1 mmol / mL to 0.5 mmoL / mL; And / or, in step g), the reaction temperature is 0-100°C.

18. The preparation method according to claim 17, characterized in that: In step g), the palladium catalyst is palladium acetate; And / or, in step g), the phosphine ligand is 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene; and / or, in step g), the alkaline reagent sodium tert-butoxide; And / or, in step g), the molar ratio of the compound 8 to the palladium catalyst is 20:1; And / or, in step g), the molar ratio of the compound 8 to the phosphine ligand is 10:1; And / or, in step g), the molar ratio of the palladium catalyst to the phosphine ligand is 1:2; And / or, in step g), the molar ratio of the compound 8 to the alkaline reagent is 1:3; And / or, in step g), the molar ratio of compound 8 to compound 9 is 1:1.1; And / or, in step g), the organic solvent used in the reaction is tetrahydrofuran; And / or, in step g), the molar volume ratio of the compound 8 to the organic solvent is 0.18 mmol / mL; And / or, in step g), the reaction temperature is 30°C.

19. The preparation method according to claim 1, characterized in that In step h), the deprotection reaction is carried out under protective gas; And / or, in step h), the removal reagent used for the deprotection group is one of sodium hydrosulfide, sodium sulfide, sodium ethanethiolate, thiophenol, sodium p-toluenethiophenol, potassium fluoride, lithium tri-sec-butylborohydride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethylsilyl iodide, cerium trichloride, ammonium cerium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and hydrochloric acid; And / or, in step h), the molar ratio of the compound 10 to the removal reagent used for the deprotection group is 1:1 to 1:8; And / or, in step h), the molar volume ratio of the compound 10 to the organic solvent is 0.05 mmol / mL to 1 mmol / mL; and / or, in step h), the organic solvent used in the deprotection reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, nitrogen methyl pyrrolidone, methanol, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate, propyl acetate and acetic acid; And / or, in step h), the temperature of the deprotection reaction is 0-110°C.

20. The preparation method according to claim 19, characterized in that In step h), the protective gas is argon; And / or, in step h), the removing agent used for the deprotection group is hydrochloric acid; And / or, in step h), the molar ratio of the compound 10 to the hydrochloric acid is 1:2; And / or, in step h), the molar volume ratio of the compound 10 to the organic solvent is 0.05 mmol / mL; And / or, in step h), the organic solvent used in the deprotection reaction is propyl acetate; And / or, in step h), the temperature of the deprotection reaction is 75°C.

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