A preparation method of CDK4 / 6 inhibitor

Abstract

The present invention relates to a method for preparing a CDK4 / 6 inhibitor, specifically a compound of formula (I): 5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)-nitrogen-(5-(piperazin-1-yl)pyrazol-2-yl)pyrimidin-2-amine. The provided method utilizes readily available, inexpensive starting materials and reagents, significantly shortens the overall reaction steps, reduces reaction time, improves overall yield, and achieves high purity of key intermediates and final products, making the method highly suitable for industrial production.

Description

[0001] Citation of Related Applications

[0002] This application claims the benefits and priority of Chinese invention patent application No. 202010571393.7 filed with the State Intellectual Property Office of the People's Republic of China on June 22, 2020, the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present application belongs to the field of drug synthesis and relates to a method for preparing a CDK4 / 6 inhibitor, specifically to a method for preparing a compound of formula (I): 5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)-nitrogen-(5-(piperazin-1-yl)pyrazol-2-yl)pyrimidine-2-amine. Background Art

[0004] The cell cycle is primarily regulated by a series of serine / threonine kinases, also known as cyclin-dependent kinases (CDKs). These kinases, by binding to their corresponding regulatory subunits, cyclins, drive cell cycle progression, genetic transcription, and normal cell division and proliferation. CDK4 / 6 are key regulators of the cell cycle, triggering the transition from the growth phase (G1) to the DNA replication phase (S1). During cell proliferation, a complex formed by cyclin D and CDK4 / 6 phosphorylates the retinoblastoma protein (Rb). Phosphorylation of the tumor suppressor protein Rb releases the transcription factor E2F, to which it binds tightly in its unphosphorylated state. E2F activation further drives transcription through the cell cycle restriction point (R point) and progression from G1 to S phase, entering the cell proliferation cycle. Therefore, inhibiting CDK4 / 6 and preventing it from forming the Cyclin D-CDK4 / 6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby inhibiting tumor proliferation. In estrogen receptor-positive (ER+) breast cancer (BC), overactivity of CDK4 / 6 is very common, and CDK4 / 6 is a key downstream target of ER signaling. Preclinical data show that dual inhibition of CDK4 / 6 and estrogen receptor (ER) signaling has a synergistic effect and can inhibit the growth of estrogen receptor-positive (ER+) breast cancer (BC) cells in the G1 phase.

[0005] WO2016141881 discloses a CDK4 / 6 inhibitor, the structure of which is shown in formula (I). The compound of formula (I) has an IC50 value of less than 1 nM for CDK4 / 6 and has good tumor inhibitory activity against breast cancer.

[0006]

[0007] WO2016141881 also discloses a method for preparing the compound of formula (I), the route of which is as follows:

[0008]

[0009] The preparation process of the compound of formula (I) has many disadvantages, including:

[0010] (i) The crude intermediates (2), (3), (4), (5), (6) and (7) are all oily compounds and require purification by silica gel column chromatography before being used in the next reaction. They are not suitable for industrial production.

[0011] (ii) The preparation processes of intermediate compounds (5), (6), (7), (8) and (9) all use metal catalysts, which result in high process costs and complicated post-processing, making them unsuitable for industrial production.

[0012] (iii) When compound (8) undergoes reduction reaction, the reduction reaction time is long because the compound (8) contains a large number of nitrogen atoms that can coordinate with metals, and is not suitable for industrial production. Summary of the Invention

[0013] The purpose of the present application is to provide a new preparation method for the compound of formula (I), in which the reagents used are economical and readily available, the post-treatment of the generated intermediates does not require silica gel column chromatography, the operation is simple, the reaction time of each step is short, the product yield is high, the product purity is high, and it is more suitable for industrial production.

[0014] In one aspect, the present application provides a method for preparing a compound of formula (I), comprising:

[0015] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0016] Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3;

[0017] Step 3: Compound SMA-3 undergoes methylation reaction to obtain compound SMA-4;

[0018] Step 4: Compound SMA-4 reacts with diboronic acid pinacol ester to obtain compound SMA-5;

[0019] Step 5: Compound SMA-5 reacts with compound SMA-9 to obtain compound SMA-6;

[0020] Step 6: Compound SMA-6 reacts with compound SMA-10 to obtain compound SMA-7;

[0021] Step 7: Compound SMA-7 is reacted to obtain a compound of formula (I).

[0022]

[0023] In some embodiments, the above step 1 is performed in the presence of a solvent and a base.

[0024] In some embodiments, the solvent in step 1 is selected from one or a mixed solvent of two or more selected from dichloromethane, tetrahydrofuran, dioxane, DMF, DMSO, acetonitrile, diethyl ether, isopropyl ether, tert-methyl ether, 2-methyltetrahydrofuran, n-hexane and n-heptane; preferably, one or a mixed solvent of two or more selected from tetrahydrofuran, dioxane and n-heptane; further preferably, tetrahydrofuran.

[0025] In some embodiments, the base in step 1 is selected from n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium bis(trimethylsilyl)amide, sodium hydrogen and lithium hydroxide; preferably lithium diisopropylamide, n-butyllithium and lithium hexamethyldisilazide; more preferably lithium diisopropylamide.

[0026] In some embodiments, the reaction temperature of the above step 1 is -75 to -20°C; preferably -75 to -50°C; more preferably -75 to -65°C.

[0027] In some embodiments, the reaction time of step 1 is 2 to 10 hours, preferably 2 to 6 hours, and more preferably 3 to 5 hours.

[0028] In some embodiments, the molar ratio of compound SMA-1 to compound SMA-8 in step 1 is 1:1-2, preferably 1:1-1.5, and more preferably 1:1-1.4. In some specific embodiments, the molar ratio of compound SMA-1 to compound SMA-8 in step 1 is approximately 1:1.33.

[0029] In some embodiments, the molar volume ratio of compound SMA-1 to solvent in step 1 is 1 mmol:0.5-1.5 mL; preferably 1 mmol:1-1.5 mL; and more preferably 1 mmol:1-1.2 mL. In some specific embodiments, the molar volume ratio of compound SMA-1 to solvent in step 1 is approximately 1 mmol:1 mL.

[0030] In some embodiments, the molar ratio of compound SMA-1 to base in step 1 is 1:1 to 3, preferably 1:1.5 to 3, and more preferably 1:1.5 to 2.1. In some specific embodiments, the molar ratio of compound SMA-1 to base in step 1 is 1:2.

[0031] In some embodiments, the above step 1 comprises: dissolving compound SMA-1 and compound SMA-8 in a solvent to form a solution, and then adding a base to react to obtain compound SMA-2.

[0032] In some embodiments, step 1 further comprises: after forming the solution, lowering the temperature to -75 to -20°C, preferably -75 to -50°C, and more preferably -75 to -65°C. In some embodiments, step 1 further comprises: adding the base at a temperature of -65°C.

[0033] In some embodiments, the above step 1 further comprises: reacting for 3 hours after the addition of the base is completed.

[0034] In some embodiments, the above step 1 further comprises: after the reaction is completed, adding an acid to the reaction solution for treatment. In some specific embodiments, the acid is hydrochloric acid (eg, 1 mol / L hydrochloric acid aqueous solution).

[0035] In some embodiments, the above step 1 further comprises: adding acid to the reaction solution for treatment, and then separating SMA-2.

[0036] In some specific embodiments, step 1 comprises: SMA-1, SMA-8, and tetrahydrofuran are stirred to dissolve and cooled to an internal temperature of -75 to -65°C. Lithium diisopropylamide is added while maintaining the internal temperature below -65°C. After addition, the internal temperature is maintained at -75 to -65°C and the reaction is allowed to proceed for 3 hours. 1 mol / L aqueous hydrochloric acid is added to the reaction solution, which is then warmed to room temperature. The layers are separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain compound SMA-2.

[0037] In the present application, the above step 1 further includes: reacting compound SMA-11 with compound SMA-12 to prepare compound SMA-8.

[0038]

[0039] In some embodiments, the above steps of preparing compound SMA-8 are performed in the presence of a solvent and a base.

[0040] In some embodiments, the solvent in the above step of preparing compound SMA-8 is selected from ethyl acetate, dichloromethane, toluene, chloroform, 1,2-dichloroethane, n-hexane, diethyl ether and methyl tert-butyl ether; preferably dichloromethane and methyl tert-butyl ether; more preferably dichloromethane.

[0041] In some embodiments, the base in the above step of preparing compound SMA-8 is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU) and triethylenediamine; preferably triethylamine and diisopropylethylamine; further preferably triethylamine.

[0042] In some embodiments, the reaction temperature of the step of preparing compound SMA-8 is 0-30° C., preferably 5-25° C., and more preferably 15-25° C. In some specific embodiments, the reaction temperature of the step of preparing compound SMA-8 is about 25° C.

[0043] In some embodiments, the reaction time of the above step of preparing compound SMA-8 is 0.5 to 5 hours, preferably 0.5 to 2 hours, and more preferably 1 to 2 hours.

[0044] In some embodiments, in the steps of preparing compound SMA-8, the molar ratio of compound SMA-11 to compound SMA-12 is 1:1 to 2, preferably 1:1 to 1.5, and more preferably 1:1 to 1.2. In some specific embodiments, the molar ratio of compound SMA-11 to compound SMA-12 is 1:1.

[0045] In some embodiments, in the steps of preparing compound SMA-8, the molar volume ratio of compound SMA-11 to solvent is 1 mmol:0.2-2 mL; preferably 1 mmol:0.5-2 mL; and more preferably 1 mmol:0.5-1 mL. In some specific embodiments, the molar volume ratio of compound SMA-11 to solvent is approximately 1 mmol:0.5 mL.

[0046] In some embodiments, in the above steps of preparing compound SMA-8, the molar ratio of compound SMA-11 to base is 1:1 to 3, preferably 1:1.5 to 3, and more preferably 1:1.5 to 2. In some specific embodiments, the molar ratio of compound SMA-11 to base is about 1:2.

[0047] In some embodiments, in the above steps of preparing compound SMA-8, compound SMA-12 is first mixed with a solvent (e.g., mixed at a temperature of -5 to 5°C), and then a base is added (e.g., a base is added at a temperature below 5°C), and then SMA-11 is added (e.g., SMA-11 is added at a temperature below 5°C).

[0048] In some embodiments, the steps for preparing compound SMA-8 are as follows: dissolve SMA-12 in dichloromethane, maintain the temperature at -5 to 5°C, add triethylamine, and maintain the temperature below 5°C. After the addition is complete, add SMA-11 while maintaining the temperature below 5°C, and react at room temperature for 1 hour.

[0049] In some embodiments, the above steps of preparing compound SMA-8 further include: treating with a base (eg, sodium bicarbonate) after the reaction is completed.

[0050] In the present application, the compound SMA-8 in the above step 1 can also be purchased through commercial channels.

[0051] In some embodiments, the above step 2 is performed in the presence of a solvent.

[0052] In some embodiments, the solvent in the above step 2 is selected from ethylene glycol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diphenyl ether, o-dichlorobenzene, cyclopentane, trimethylbenzene, diethylene glycol dimethyl ether and N-methylpyrrolidone; preferably DMF and ethylene glycol; more preferably ethylene glycol.

[0053] In some embodiments, the above step 2 further comprises the step of removing water during the reaction.

[0054] In some embodiments, the above step 2 is: after the compound SMA-2 reacts with hydrazine hydrate for a period of time, the water is removed and the reaction is continued.

[0055] In some embodiments, the reaction temperature of step 2 is 100-200°C, preferably 150-200°C.

[0056] In some embodiments, Step 2 is performed by first reacting compound SMA-2 with hydrazine hydrate at 180-200°C or under reflux, followed by a reaction at 150°C. Specifically, water is removed between the two reaction stages. In some embodiments, the reaction time in Step 2 is 2-15 hours, preferably 5-12 hours, and more preferably 10-12 hours.

[0057] In some embodiments, step 2 is as follows: compound SMA-2 and hydrazine hydrate are first reacted at a temperature of 180-200°C or under reflux for 2 hours, and then reacted at a temperature of 150°C for 10 hours. Specifically, a step of removing water is included between the two reactions.

[0058] In some embodiments, the molar ratio of compound SMA-2 to hydrazine hydrate in step 2 is 1:1-3; preferably 1:1.5-3; and more preferably 1:1.5-2.

[0059] In some embodiments, the molar volume ratio of compound SMA-2 to the solvent in step 2 is 1 mmol: 0.5-1.5 mL; preferably 1 mmol: 1-1.5 mL; further preferably 1 mmol: 1-1.2 mL.

[0060] In some embodiments, the above step 2 is: SMA-2 and hydrazine hydrate are refluxed in the presence of ethylene glycol for 2 hours, water in the reaction system is removed, and the reaction is carried out at 150° C. for 10 hours to obtain compound SMA-3.

[0061] In some embodiments, the above step 2 further comprises the step of adding water to the reaction system after the reaction is completed to precipitate compound SMA-3, and further comprises the step of slurrying with purified water.

[0062] In some embodiments, the above step 3 is performed in the presence of a methylating agent and a solvent.

[0063] In some embodiments, the methylating agent in the above step 3 is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, tetramethylammonium fluoride, trimethyl phosphate, trimethyloxonium tetrafluoroborate and 1-methyl-3-p-tolyltriazine; preferably iodomethane and trimethyloxonium tetrafluoroborate; further preferably trimethyloxonium tetrafluoroborate.

[0064] In some embodiments, the solvent in step 3 is selected from one or a mixture of two or more of ethyl acetate, dichloromethane, and acetone; preferably, one or a mixture of two or more of ethyl acetate and dichloromethane. In some specific embodiments, the solvent in step 3 is ethyl acetate first and then dichloromethane. In some specific embodiments, the solvent in step 3 is ethyl acetate.

[0065] In some embodiments, the above step 3 can also be performed in the presence of a methylating agent, a base and a solvent.

[0066] In some embodiments, the base in step 3 is selected from potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium bicarbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide; preferably sodium bicarbonate and sodium hydroxide; more preferably sodium bicarbonate.

[0067] In some embodiments, the reaction temperature of step 3 is controlled at 10-30°C, preferably 20-30°C, and more preferably 25-30°C.

[0068] In some embodiments, the reaction time of step 3 is 5 to 12 hours, preferably 8 to 12 hours, and more preferably 8 to 10 hours. In some specific embodiments, the reaction time of step 3 is about 8 hours.

[0069] In some embodiments, the above step 3 is: reacting compound SMA-3 with trimethyloxonium tetrafluoroboric acid to obtain onium tetrafluoroborate salt of compound SMA-4, and reacting the onium tetrafluoroborate salt of compound SMA-4 to obtain compound SMA-4.

[0070] In some embodiments, the step of reacting the onium tetrafluoroborate salt of the above-mentioned compound SMA-4 to obtain the compound SMA-4 can be carried out in the presence of a base (eg, sodium bicarbonate).

[0071] In some embodiments, the preparation of the onium tetrafluoroborate salt of the compound SMA-4 is carried out in the presence of a solvent selected from ethyl acetate and acetone; preferably ethyl acetate.

[0072] In some embodiments, the step of reacting the onium tetrafluoroborate salt of the above compound SMA-4 to obtain compound SMA-4 is carried out in the presence of a solvent selected from dichloromethane and ethyl acetate; preferably dichloromethane; or preferably ethyl acetate.

[0073] In some embodiments, the above step 3 is: compound SMA-3 reacts with trimethyloxonium tetrafluoroboric acid in the presence of ethyl acetate to obtain the tetrafluoroborate salt of compound SMA-4, and the tetrafluoroborate salt of compound SMA-4 reacts in the presence of dichloromethane and a base to obtain compound SMA-4.

[0074] In some embodiments, the above step 3 is: compound SMA-3 reacts with trimethyloxonium tetrafluoroboric acid in the presence of ethyl acetate at a temperature of 25-30°C to obtain a tetrafluoroborate salt of compound SMA-4, isolates the tetrafluoroborate salt of compound SMA-4, and reacts the tetrafluoroborate salt of compound SMA-4 with sodium bicarbonate in the presence of dichloromethane and water to obtain compound SMA-4.

[0075] In some embodiments, the molar ratio of compound SMA-3 to the methylating agent in step 3 is 1:1 to 3; preferably 1:1 to 2; and more preferably 1:1 to 1.2.

[0076] In some embodiments, the molar ratio of compound SMA-3 to the base in step 3 is 1:1-5; preferably 1:2-4; more preferably 1:2.5-3.5.

[0077] In some embodiments, the above step 4 is performed in the presence of a catalyst, a base and a solvent.

[0078] In some embodiments, the catalyst in step 4 is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, 1,3-bis(diphenylphosphino)propanepalladium dichloride, 1,4-bis(diphenylphosphino)butanepalladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride or tris(dibenzylideneacetone)dipalladium; preferably bis(triphenylphosphine)palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; further preferably 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride.

[0079] In some embodiments, the base in step 4 is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine or N-methylpiperidine; preferably potassium acetate or cesium carbonate; more preferably potassium acetate.

[0080] In some embodiments, the solvent in step 4 is selected from one or a mixed solvent of two or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water; preferably tetrahydrofuran and dioxane; more preferably dioxane.

[0081] In some embodiments, the reaction temperature of step 4 is 80-120° C., preferably 85-105° C., and more preferably 90-105° C. In some specific embodiments, the reaction temperature of step 4 is 90-95° C.

[0082] In some embodiments, the reaction time of step 4 is 5 to 15 hours, preferably 8 to 12 hours, and more preferably 8 to 10 hours. In some specific embodiments, the reaction time of step 4 is about 9 hours.

[0083] In some embodiments, the molar ratio of compound SMA-4 to diboronic acid pinacol ester in step 4 is 1:1-3; preferably 1:1-2; more preferably 1:1-1.5.

[0084] In some embodiments, the molar ratio of compound SMA-4 to the catalyst in step 4 is 1:0.001-0.01; preferably 1:0.002-0.008; further preferably 1:0.004-0.006.

[0085] In some embodiments, the molar ratio of compound SMA-4 to the base in step 4 is 1:1-3; preferably 1:1-2; and more preferably 1:1.5-2.

[0086] In some embodiments, the molar volume ratio of compound SMA-4 to the solvent in step 4 is 1 mmol: 1-2 mL; preferably 1 mmol: 1-1.5 mL; further preferably 1 mmol: 1.2-1.5 mL.

[0087] In some embodiments, the above step 4 is: compound SMA-4 is reacted with diboronic acid pinacol ester in the presence of 1,4-dioxane, potassium acetate and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride to obtain compound SMA-5.

[0088] In some embodiments, the above step 4 is: compound SMA-4 reacts with diboronic acid pinacol ester in the presence of 1,4-dioxane, potassium acetate and 1,1'-bis(diphenylphosphino)ferrocenedaphtalate dichloride at a reaction temperature of 90-95° C. for 9 hours to obtain compound SMA-5.

[0089] In some embodiments, the above step 5 is performed in the presence of a catalyst, a base and a solvent.

[0090] In some embodiments, the catalyst in step 5 is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride or tris(dibenzylideneacetone)dipalladium; preferably bis(triphenylphosphine)palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; further preferably 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride.

[0091] In some embodiments, the base in step 5 is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine or N-methylpiperidine; preferably cesium carbonate or potassium carbonate; more preferably potassium carbonate.

[0092] In some embodiments, the solvent in step 5 is selected from one or a mixed solvent of two or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water; preferably dioxane and toluene; more preferably dioxane.

[0093] In some embodiments, the reaction temperature of step 5 is 80-120°C; preferably 85-105°C; more preferably 90-105°C.

[0094] In some embodiments, the reaction time of step 5 is 5 to 15 hours, preferably 8 to 12 hours, and more preferably 10 to 12 hours.

[0095] In some embodiments, the molar ratio of compound SMA-5 to compound SMA-9 in step 5 is 1:1-2; preferably 1:1-1.5; and more preferably 1:1-1.2.

[0096] In some embodiments, the molar ratio of compound SMA-5 to the catalyst in step 5 is 1:0.005-0.05; preferably 1:0.01-0.05; and more preferably 1:0.01-0.03.

[0097] In some embodiments, the molar ratio of compound SMA-5 to the base in step 5 is 1:1-3; preferably 1:1-2; and more preferably 1:1.5-2.

[0098] In some embodiments, the molar volume ratio of compound SMA-5 to the solvent in step 5 is 1 mmol: 0.1-2 mL; preferably 1 mmol: 0.2-1 mL; further preferably 1 mmol: 0.2-0.5 mL.

[0099] In some embodiments, the above step 5 is: compound SMA-5 and compound SMA-9 are reacted in the presence of potassium carbonate, water and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride at a temperature of 90-95° C. to obtain compound SMA-6.

[0100] In some embodiments, step 5 further comprises: after the reaction is completed, adding a mixed solution of ethanol and water for treatment. The process further comprises adding the solid separated after treatment to a mixed system of water and dichloromethane for treatment. The process further comprises separating the organic phase after treatment and treating the organic phase with anhydrous sodium sulfate and activated carbon.

[0101] In some embodiments, the above step 5 further comprises: purifying compound SMA-6 with ethyl acetate.

[0102] In some embodiments, the above step 6 is performed in the presence of a catalyst, a base and a solvent.

[0103] In some embodiments, the catalyst in step 6 is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride and tris(dibenzylideneacetone)dipalladium; preferably palladium acetate and tris(dibenzylideneacetone)dipalladium; more preferably palladium acetate.

[0104] In some embodiments, in the above step 6, the catalyst is selected from palladium acetate and tris(dibenzylideneacetone)dipalladium, wherein the catalyst needs to be used in the presence of a ligand, and the ligand is selected from 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,1'-binaphthol and 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; preferably 4,5-bisdiphenylphosphine-9,9-dimethylxanthene and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; further preferably 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0105] In some embodiments, the above step 6 is performed in the presence of palladium acetate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, a base and a solvent.

[0106] In some embodiments, the base in step 6 is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine and N-methylpiperidine; preferably sodium carbonate, potassium carbonate and cesium carbonate; more preferably cesium carbonate.

[0107] In some embodiments, the solvent in step 6 is selected from one or a mixed solvent of two or more selected from dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water; preferably tetrahydrofuran and dioxane; further preferably dioxane.

[0108] In some embodiments, the reaction temperature of step 6 is 80-150° C., preferably 80-120° C., and more preferably 100-120° C. In some specific embodiments, the reaction temperature of step 6 is about 110° C.

[0109] In some embodiments, the reaction time of step 6 is 3 to 10 hours, preferably 3 to 8 hours, and more preferably 4 to 6 hours. In some specific embodiments, the reaction time of step 6 is about 5 hours.

[0110] In some embodiments, the molar ratio of compound SMA-6 to compound SMA-10 in step 6 is 1:1-2; preferably 1:1-1.5; and more preferably 1:1-1.2.

[0111] In some embodiments, the molar ratio of compound SMA-6 to the catalyst in step 6 is 1:0.01-0.1; preferably 1:0.02-0.06; and more preferably 1:0.02-0.04.

[0112] In some embodiments, the molar ratio of compound SMA-6 to the ligand in step 6 is 1:0.01-0.1; preferably 1:0.02-0.06; and more preferably 1:0.04-0.06.

[0113] In some embodiments, the molar ratio of compound SMA-6 to the base in step 6 is 1:1-3; preferably 1:1.5-3; and more preferably 1:1.5-2.

[0114] In some embodiments, the molar volume ratio of compound SMA-6 to the solvent in step 6 is 1 mmol:1-8 mL; preferably 1 mmol:2-6 mL; further preferably 1 mmol:3-4 mL.

[0115] In some embodiments, the above step 6 is: compound SMA-6 and compound SMA-10 are reacted in the presence of cesium carbonate, 1,4-dioxane, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and palladium acetate at a temperature of 110° C. to obtain compound SMA-7.

[0116] In some embodiments, the above step 6 further comprises: adding dichloromethane to the reaction system after the reaction is completed, further comprising adding sodium sulfate and mercapto silica gel, stirring, and filtering.

[0117] In some embodiments, the above step 6 further comprises the step of slurrying the compound SMA-7 with ethyl acetate.

[0118] In the present application, compound SMA-10 can be prepared by referring to the method disclosed in the specification of WO2018045993.

[0119] In the present application, compound SMA-10 can also be purchased through commercial channels.

[0120] In some embodiments, step 7 is performed in the presence of an acid and a solvent.

[0121] In some embodiments, the acid in step 7 is selected from hydrogen chloride, and the solvent in step 7 is selected from methanol, ethanol, and isopropanol; preferably, methanol.

[0122] In some specific embodiments, the acid in step 7 is selected from hydrogen chloride, and the solvent in step 7 is selected from methanol. In step 7, after removing the protecting group of compound SMA-7, the hydrochloride of compound of formula (I) is first obtained; further, the hydrochloride of compound of formula (I) is neutralized with a base to obtain compound of formula (I). In some embodiments, the base used to neutralize the hydrochloride of compound of formula (I) is selected from aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, or aqueous potassium carbonate; preferably aqueous sodium hydroxide.

[0123] In the present application, the deprotection reaction of compound SMA-7 to obtain the compound of formula (I) can also be prepared by referring to the method disclosed in Example 3 of WO201614188.

[0124] The present application also provides a method for preparing an intermediate SMA-6, comprising:

[0125] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0126] Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3;

[0127] Step 3: Compound SMA-3 undergoes methylation reaction to obtain compound SMA-4;

[0128] Step 4: Compound SMA-4 reacts with diboronic acid pinacol ester to obtain compound SMA-5;

[0129] Step 5: Compound SMA-5 reacts with compound SMA-9 to obtain compound SMA-6.

[0130]

[0131] In some embodiments, the reaction conditions of step 1, step 2, step 3, step 4 and step 5 in the preparation method of the intermediate SMA-6 are the same as those described in step 1, step 2, step 3, step 4 and step 5 in the preparation method of the compound of formula (I) in this application.

[0132] The present application also provides a method for preparing an intermediate SMA-6 and its use in the preparation of a compound of formula (I).

[0133] The present application also provides a method for preparing the intermediate SMA-3, comprising:

[0134] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0135] Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3.

[0136]

[0137] In some embodiments, the reaction conditions of step 1 and step 2 in the method for preparing the intermediate SMA-3 are the same as those described in step 1 and step 2 in the method for preparing the compound of formula (I) in the present application.

[0138] The present application also provides a method for preparing the intermediate SMA-3 and its use in the preparation of the compound of formula (I).

[0139] The present application also provides a method for preparing an intermediate SMA-4, comprising:

[0140] Compound SMA-3 undergoes methylation reaction to obtain compound SMA-4.

[0141]

[0142] In some embodiments, the reaction conditions in the preparation method of the intermediate SMA-4 are as described in step 3 of the preparation method of the compound of formula (I) in this application.

[0143] In a specific embodiment, the preparation method of the intermediate SMA-4 includes: reacting compound SMA-3 with trimethyloxonium tetrafluoroboric acid to generate an onium salt intermediate compound SMA-3' (onium tetrafluoroborate salt of compound SMA-4), and further hydrolyzing the onium salt intermediate compound SMA-3' to obtain compound SMA-4.

[0144]

[0145] In some embodiments, the formation of the onium salt intermediate compound SMA-3' is carried out in the presence of a solvent.

[0146] In some embodiments, the solvent for generating the onium salt intermediate compound SMA-3' is selected from ethyl acetate and acetone, preferably ethyl acetate.

[0147] In some embodiments, the reaction temperature for generating the onium salt intermediate compound SMA-3' is controlled at 10-30°C, preferably 20-30°C, and more preferably 25-30°C.

[0148] In some embodiments, the reaction time for generating the onium salt intermediate compound SMA-3' is 5 to 12 hours, preferably 8 to 12 hours, and more preferably 8 to 10 hours.

[0149] In some embodiments, the molar ratio of compound SMA-3 to trimethyloxonium tetrafluoroborate in the formation of the onium salt intermediate compound SMA-3' is 1:1-3; preferably 1:1-2; more preferably 1:1-1.2.

[0150] In some embodiments, the molar volume ratio of compound SMA-3 to solvent in the formation of the onium salt intermediate compound SMA-3' is 1 mmol: 1-5 mL; preferably 1 mmol: 2-4 mL; further preferably 1 mmol: 2-3 mL.

[0151] In some embodiments, the hydrolysis of the above-mentioned onium salt intermediate compound SMA-3' is carried out in the presence of a base and a solvent.

[0152] In some embodiments, the base for hydrolysis of the onium salt intermediate compound SMA-3' is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide; preferably sodium bicarbonate and sodium hydroxide; further preferably sodium bicarbonate.

[0153] In some embodiments, the base used for hydrolysis of the onium salt intermediate compound SMA-3' is an aqueous solution thereof.

[0154] In some embodiments, the solvent used for hydrolysis of the onium salt intermediate compound SMA-3' is the same as the solvent used for the generation of the onium salt intermediate.

[0155] In some embodiments, the solvent for hydrolysis of the onium salt intermediate compound SMA-3' is selected from dichloromethane and ethyl acetate; preferably dichloromethane.

[0156] In some embodiments, the solvents required for the formation and hydrolysis of the onium salt intermediate compound SMA-3' are the same or different.

[0157] In some embodiments, the molar ratio of the onium salt intermediate compound SMA-3' to the base is 1:1-5; preferably 1:1-3; more preferably 1:2-3.

[0158] In some embodiments, the reaction time for hydrolysis of the onium salt intermediate compound SMA-3' is 0.5 to 3 hours, preferably 0.5 to 1 hour.

[0159] The present application also provides the use of the preparation method of the intermediate SMA-4 in the preparation of the compound of formula (I).

[0160] The preparation of the compound of formula (I) of the present application may further include purification of the crude product.

[0161] The compound SMA-1, hydrazine hydrate, bipyraclostrobin and compound SMA-9 in the present application can all be purchased through commercial channels.

[0162] The preparation method of the compound of formula (I) and its intermediates provided in this application has the following advantages:

[0163] (i) Silica gel column chromatography is not used in the post-treatment of the intermediates prepared in this application, and the post-treatment operation is simple, economical and readily available.

[0164] (ii) The metal catalyst used in the preparation process of the compound of formula (I) of the present application has fewer reaction steps and less dosage than the prior art, which is more economical, and the metal residue in the final product is also correspondingly less.

[0165] (iii) Compared with the prior art, the preparation of the compound of formula (I) of the present application reduces the step of allyl reduction, greatly shortens the reaction time, and avoids the use of rhodium catalyst, which is more economical and environmentally friendly.

[0166] (iv) The starting materials and reagents for preparing the compound of formula (I) of the present application are cheap and readily available, the overall reaction steps are greatly shortened, the reaction time is shortened, the overall yield is improved, and the purity of the key intermediates and the final product is high, which is very suitable for industrial production.

[0167] In the present application, LDA refers to lithium diisopropylamide; DMF refers to N,N-dimethylformamide; DMSO refers to dimethyl sulfoxide; DBU refers to 1,8-diazabicycloundec-7-ene; DMAP refers to 4-dimethylaminopyridine; Pin2B2 refers to pinacol diboron; Pd(dppf)Cl2 refers to 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride); TLC refers to thin layer chromatography; and HPLC refers to high performance liquid chromatography. DETAILED DESCRIPTION

[0168] The following specific embodiments are intended to enable those skilled in the art to more clearly understand and implement the present application. They should not be considered as limitations of the present application, but are merely exemplary descriptions and typical representatives of the present application.

[0169] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0170] All solvents used in this application were commercially available and used without further purification.

[0171] Preparation of compound SMA-8

[0172]

[0173] To a 100L reactor, add N,O-dimethylhydroxylamine hydrochloride (SMA-12) (5.0kg), add dichloromethane (26L) and stir to dissolve, cool to an internal temperature of -5 to 5°C, slowly add triethylamine (10.4kg), control the internal temperature below 5°C during the addition, and after the addition is complete, add isobutyryl chloride (SMA-11) (5.46kg) dropwise while controlling the internal temperature below 5°C. Close the dripping and stir at room temperature for 1 hour. TLC detection shows that the reaction of the raw material isobutyryl chloride is complete. The reaction solution is slowly poured into a saturated sodium bicarbonate aqueous solution (77L), separated, and the organic phase is washed with 1mol / L hydrochloric acid (26L) and a 10% sodium chloride aqueous solution (26L) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a total of 5.5kg of compound SMA-8 with a yield of 81.8%.

[0174] Preparation of compounds of formula (I)

[0175]

[0176] Preparation of compound SMA-2

[0177] To a 100L stainless steel reactor, 4-fluorobromobenzene (SMA-1) (4kg), N,O-dimethylisobutyramide (SMA-8) (4.0kg), and tetrahydrofuran (23.2L) were added, stirred, dissolved, and cooled to an internal temperature of -75 to -65°C. LDA (2mol / L, 23.2L) was slowly added dropwise, maintaining the internal temperature below -65°C. After completion of the addition, the internal temperature was maintained at -75 to -65°C and stirred for 3 hours. 1mol / L aqueous hydrochloric acid solution (46L) was added dropwise to the reaction solution. After completion of the addition, the temperature was slowly warmed to room temperature. The layers were separated, and the aqueous phase was extracted with ethyl acetate (15L). The organic phases were combined, washed with water (10L x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 6.18kg of compound SMA-2 with a yield of 85.7%.

[0178] Preparation of compound SMA-3

[0179] Compound SMA-2 (6.0 kg), ethylene glycol (23 L), and 80% hydrazine hydrate (2.4 kg) were added to a 50 L reactor. After addition, the mixture was stirred and refluxed for 2 hours. The water in the reaction system was removed and the reaction was continued at 150 ° C for 10 hours. The temperature was slowly lowered to room temperature, 23 L of purified water was added, and the mixture was stirred for 1 hour to crystallize. The filter cake was slurried with 25 L of purified water, filtered, and dried with air at 50 ° C to obtain 3.2 kg of compound SMA-3, with a yield of 70%.

[0180] Preparation of compound SMA-4

[0181] Compound SMA-3 (3 kg) and ethyl acetate (30 L) were added to a 50 L reactor, and trimethyloxonium tetrafluoroboric acid (2.06 kg) was added under nitrogen protection. After the addition, the mixture was stirred at 25-30 ° C for 8 hours, filtered, and the filter cake was slurried with 40 L of n-hexane for 3 hours, filtered, and air-dried to obtain 3.3 kg of tetrafluoroborate salt of compound SMA-4 (SMA-3') with a yield of 77.1%.

[0182] To a 5 L beaker, add the tetrafluoroborate onium salt of the above-mentioned compound SMA-4 (135 g), and then add 1 L of saturated NaHCO3 solution and 1 L of dichloromethane respectively. Stir for 0.5 hours, separate the liquids, wash once with 500 mL of saturated NaCl solution, separate the liquids, and concentrate the organic phase to dryness to obtain compound SMA-4 for use.

[0183] Preparation of compound SMA-5

[0184] To a 1L four-necked flask, add the above-obtained compound SMA-4, 1,4-dioxane (500 mL), pinacol diboron (151 g), and potassium acetate (78 g). Degas the mixture and replace it with nitrogen three times. Under nitrogen, add Pd(dppf)Cl₂CH₂Cl₂ (1.5 g). After addition, heat the mixture to an internal temperature of 90-95°C and stir for 9 hours. Cool the mixture to room temperature, filter, and rinse with 1,4-dioxane (50 mL) to obtain the filtrate containing compound SMA-5 for later use.

[0185] Preparation of compound SMA-6

[0186] The filtrate containing compound SMA-5 was transferred to a 1L four-necked flask, and 2,4-dichloro-5-fluoropyrimidine (SMA-9) (68 g) and potassium carbonate (111 g) were added in sequence. 100 mL of purified water was added under stirring, and the mixture was degassed and replaced with nitrogen three times. Pd(dppf)Cl2 was added under nitrogen protection. After the addition of CH2Cl2 (3.3 g), the temperature was raised to 90-95°C and stirred for 12 hours, then cooled to room temperature, concentrated, slurried with 500 mL of ethanol aqueous solution (ethanol / water = 1 / 1) for 1 hour, filtered, and the solid was added to a mixture of 500 mL of water and 300 mL of dichloromethane, stirred to dissolve, separated, and the aqueous phase was extracted with dichloromethane (100 mL*2). The organic phases were combined, dehydrated and decolorized with anhydrous Na2SO4 and 3% activated carbon for 0.5 hour, filtered, and concentrated to dryness to obtain 75 g of a crude product. The crude product was slurried with ethyl acetate (200 mL) for 0.5 hour, filtered, and dried to obtain 60 g of pure compound SMA-6 with a purity of 99.1% and a yield of 50.1%.

[0187] Preparation of compound SMA-7

[0188] Compound SMA-6 (1.70 kg), compound SMA-10 (1.57 kg), cesium carbonate (3.61 kg), 1,4-dioxane (17 L), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (158.39 g), and palladium acetate (37.30 g) were added to a 50 L reactor in sequence, protected by nitrogen, stirred at 110 ° C for 5 hours, cooled, and 20 L of dichloromethane was added to the reaction mixture and stirred for 30 minutes. The mixture was filtered through celite, washed twice with water, and sodium sulfate and mercapto silica gel (5%) were added and stirred and filtered. The filtrate was further added with 5% mercapto silica gel and stirred and filtered. The filtrate was concentrated to dryness, ethyl acetate (17 L) was added and slurried for 2 hours, filtered with suction, and dried to obtain compound SMA-7, which was directly used in the next reaction.

[0189] Preparation of compounds of formula (I)

[0190] 1.9 kg of hydrogen chloride gas was introduced into a methanol (12.5 L) solution to obtain a 4M hydrogen chloride / methanol solution. 12.5 L of methanol and compound SMA-7 were added to the reactor in sequence at 20 ° C to obtain a suspension. 12.5 L of 4M hydrogen chloride / methanol solution was then added to a 50 L reactor, and the system temperature was raised to 50 ° C. After 10 minutes, solids precipitated and a large amount of gas was generated. The reaction system was stirred at 50 ° C for 17.5 hours. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to 20 ° C and filtered, and the filter cake was washed with 5 L of methanol. The resulting filter cake was dried in a vacuum oven at 50 ° C for 42 hours to obtain a crude hydrochloride salt of the compound of formula (I), which was directly subjected to the next step of the reaction.

[0191] At 20°C, 2.60 kg of the crude hydrochloride of the compound of formula (I) and 7.8 L of ethanol were added sequentially to a 50 L reactor. The resulting turbid solution was heated to 75°C. 12.4 L of a 5% aqueous sodium hydroxide solution was added dropwise to the reactor to adjust the pH to approximately 11. The reaction system was cooled to 68°C. After approximately 5 minutes, solids began to precipitate. The reaction system was heated to 75°C and stirred at this temperature for 1 hour. The reaction system was cooled to 20°C, filtered, and the filter cake was washed with 10 L of water twice. The resulting filter cake was dried in a vacuum oven at 60°C for 48 hours to obtain 1.9 kg of the compound of formula (I) with a yield of 83.4% and a purity of 98.9%.

Claims

1. A method for preparing a compound of formula (I), comprising: Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2; Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3; Step 3: Compound SMA-3 undergoes methylation reaction to obtain compound SMA-4; Step 4: Compound SMA-4 reacts with diboronic acid pinacol ester to obtain compound SMA-5; Step 5: Compound SMA-5 reacts with compound SMA-9 to obtain compound SMA-6; Step 6: Compound SMA-6 reacts with compound SMA-10 to obtain compound SMA-7; Step 7: Compound SMA-7 is reacted to obtain a compound of formula (I); 2. The method for preparing the compound of formula (I) according to claim 1, wherein Step 1 is carried out in the presence of a solvent and a base; the solvent is selected from one or a mixed solvent of two or more of dichloromethane, tetrahydrofuran, dioxane, DMF, DMSO, acetonitrile, diethyl ether, isopropyl ether, methyl tert-ether, 2-methyltetrahydrofuran, n-hexane and n-heptane; The base is selected from n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium bis(trimethylsilyl)amide, sodium hydrogen and lithium hydroxide.

3. The method for preparing the compound of formula (I) according to claim 2, wherein Step 1 is carried out in the presence of a solvent and a base; the solvent is selected from one or a mixed solvent of two or more of tetrahydrofuran, dioxane and n-heptane; The base is selected from lithium diisopropylamide, n-butyllithium and lithium hexamethyldisilazide.

4. The method for preparing the compound of formula (I) according to claim 3, wherein Step 1 is carried out in the presence of a solvent and a base; the solvent is selected from tetrahydrofuran; The base is selected from lithium diisopropylamide.

5. A method for preparing a compound of formula (I) according to any one of claims 1 to 4, wherein The molar ratio of compound SMA-1 to compound SMA-8 is 1:1-2.

6. The method for preparing the compound of formula (I) according to claim 5, wherein The molar ratio of compound SMA-1 to compound SMA-8 is 1:1 to 1.

5.

7. The method for preparing the compound of formula (I) according to claim 6, wherein The molar ratio of compound SMA-1 to compound SMA-8 is 1:1 to 1.

4.

8. A method for preparing a compound of formula (I) according to any one of claims 1 to 4, wherein The molar volume ratio of compound SMA-1 to the solvent is 1 mmol:0.5-1.5 mL.

9. The method for preparing the compound of formula (I) according to claim 8, wherein The molar volume ratio of compound SMA-1 to the solvent is 1 mmol:1-1.5 mL.

10. The method for preparing the compound of formula (I) according to claim 9, wherein The molar volume ratio of compound SMA-1 to the solvent is 1 mmol:1-1.2 mL.

11. A method for preparing a compound of formula (I) according to any one of claims 1 to 4, wherein: The molar ratio of SMA-1 to the base is 1:1-3.

12. A method for preparing the compound of formula (I) according to claim 11, wherein The molar ratio of SMA-1 to alkali is 1:1.5-3.

13. A method for preparing the compound of formula (I) according to claim 12, wherein: The molar ratio of SMA-1 to the alkali is 1:1.5-2.

1.

14. A method for preparing the compound of formula (I) according to claim 1, wherein Step 2 is carried out in the presence of a solvent; the solvent is selected from ethylene glycol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diphenyl ether, o-dichlorobenzene, sulfolane, trimethylbenzene, diethylene glycol dimethyl ether and N-methylpyrrolidone.

15. A method for preparing the compound of formula (I) according to claim 14, wherein: Step 2 is carried out in the presence of a solvent; the solvent is selected from DMF and ethylene glycol.

16. A method for preparing the compound of formula (I) according to claim 15, wherein: Step 2 is carried out in the presence of a solvent; the solvent is selected from ethylene glycol.

17. A method for preparing the compound of formula (I) according to claim 1, wherein: Step 2 is: after the compound SMA-2 reacts with hydrazine hydrate for a period of time, water is removed and the reaction is continued; wherein, the compound SMA-2 and hydrazine hydrate are first reacted at a temperature of 180 to 200° C. or under reflux conditions, and then reacted at a temperature of 150° C.

18. A method for preparing a compound of formula (I) according to any one of claims 14 to 17, wherein: In step 2, the molar ratio of compound SMA-2 to hydrazine hydrate is 1:1-3.

19. A method for preparing the compound of formula (I) according to claim 18, wherein: In step 2, the molar ratio of compound SMA-2 to hydrazine hydrate is 1:1.5-3.

20. The method for preparing the compound of formula (I) according to claim 19, wherein In step 2, the molar ratio of compound SMA-2 to hydrazine hydrate is 1:1.5-2.

21. A method for preparing a compound of formula (I) according to any one of claims 14 to 17, wherein: In step 2, the molar volume ratio of compound SMA-2 to the solvent is 1 mmol:0.5-1.5 mL.

22. A method for preparing the compound of formula (I) according to claim 21, wherein: In step 2, the molar volume ratio of compound SMA-2 to the solvent is 1 mmol:1-1.5 mL.

23. A method for preparing the compound of formula (I) according to claim 22, wherein: In step 2, the molar volume ratio of compound SMA-2 to the solvent is 1 mmol:1-1.2 mL.

24. A method for preparing the compound of formula (I) according to claim 1, wherein: Step 3 is carried out in the presence of a methylating agent and a solvent; the methylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, tetramethylammonium fluoride, trimethyl phosphate, trimethyloxonium tetrafluoroborate and 1-methyl-3-p-tolyltriazine; The solvent is selected from one or a mixed solvent of two or more of ethyl acetate, dichloromethane and acetone.

25. A method for preparing the compound of formula (I) according to claim 24, wherein: Step 3 is carried out in the presence of a methylating agent and a solvent; the methylating agent is selected from iodomethane and trimethyloxonium tetrafluoroboric acid; The solvent is selected from one or a mixed solvent of two or more of ethyl acetate and dichloromethane.

26. A method for preparing the compound of formula (I) according to claim 25, wherein: Step 3 is carried out in the presence of a methylating agent and a solvent; the methylating agent is selected from trimethyloxonium tetrafluoroborate.

27. A method for preparing the compound of formula (I) according to claim 1, wherein: Step 4 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride or tris(dibenzylideneacetone)dipalladium; The base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine or N-methylpiperidine; The solvent is selected from one or a mixed solvent of two or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

28. A method for preparing the compound of formula (I) according to claim 27, wherein: Step 4 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from bis(triphenylphosphine)palladium dichloride or 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride; The base is selected from potassium acetate or cesium carbonate; The solvent is selected from tetrahydrofuran and dioxane.

29. A method for preparing the compound of formula (I) according to claim 28, wherein: Step 4 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; The base is selected from potassium acetate; The solvent is selected from dioxane.

30. A method for preparing the compound of formula (I) according to claim 1, wherein: Step 5 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride or tris(dibenzylideneacetone)dipalladium; The base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine or N-methylpiperidine; The solvent is selected from one or a mixed solvent of two or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

31. A method for preparing a compound of formula (I) according to claim 30, wherein: Step 5 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from bis(triphenylphosphine)palladium dichloride or 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride; The base is selected from cesium carbonate or potassium carbonate; The solvent is selected from dioxane and toluene.

32. A method for preparing a compound of formula (I) according to claim 31, wherein Step 5 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; The base is selected from potassium carbonate; The solvent is selected from dioxane.

33. A method for preparing the compound of formula (I) according to claim 1, wherein Step 6 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride and tris(dibenzylideneacetone)dipalladium; The base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine and N-methylpiperidine; The solvent is selected from one or a mixed solvent of two or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

34. A method for preparing a compound of formula (I) according to claim 33, wherein: Step 6 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from palladium acetate and tris(dibenzylideneacetone)dipalladium; The base is selected from sodium carbonate, potassium carbonate and cesium carbonate; The solvent is selected from tetrahydrofuran and dioxane.

35. A method for preparing a compound of formula (I) according to claim 34, wherein: Step 6 is carried out in the presence of a catalyst, a base and a solvent; the catalyst is selected from palladium acetate; The base is selected from cesium carbonate; The solvent is selected from dioxane.

36. A method for preparing the compound of formula (I) according to claim 1, wherein the method for preparing the intermediate SMA-6 comprises: Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2; Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3; Step 3: Compound SMA-3 undergoes methylation reaction to obtain compound SMA-4; Step 4: Compound SMA-4 reacts with diboronic acid pinacol ester to obtain compound SMA-5; Step 5: Compound SMA-5 reacts with compound SMA-9 to obtain compound SMA-6; 37. Use of the preparation method of the intermediate SMA-6 according to claim 36 in the preparation of the compound of formula (I),

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