Preparation method of CDK4 / 6 inhibitor

Abstract

The invention relates to a preparation method of a CDK4 / 6 inhibitor, in particular to a preparation method of a compound as shown in a formula (I): 5-fluoro-4-(3-isopropyl-2-methyl-2H-indazole-5-yl)-nitrogen-(5-(piperazine-1-yl) pyrazole-2-yl) pyrimidine-2-amine. According to the preparation method provided by the invention, the initial raw materials and reagents are cheap and easily available, the total reaction steps are greatly shortened, the reaction time is shortened, the total yield is improved, the purity of key intermediates and final products is relatively high, and the preparation method is very suitable for industrial production.

Description

[0001] This application is a divisional application of the application filed on June 21, 2021, with application number 202180041423.6 and invention title "A method for preparing a CDK4 / 6 inhibitor".

[0002] Citation of relevant applications

[0003] This application claims the benefit and priority of Chinese 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 incorporated herein by reference. Technical Field

[0004] This application belongs to the field of drug synthesis and relates to a method for preparing a CDK4 / 6 inhibitor, specifically relating to the preparation method of compound (I): 5-fluoro-4-(3-isopropyl-2-methyl-2H-indazole-5-yl)-nitro-(5-(piperazin-1-yl)pyrazol-2-yl)pyrimidine-2-amine. Background Technology

[0005] Cell cycle regulation is primarily influenced by a series of serine / threonine kinases, also known as cyclin-dependent kinases (CDKs). These kinases, through their binding to their corresponding regulatory subunits cyclins, drive cell cycle progression, transcription of genetic information, and normal cell division and proliferation. CDK4 / 6 are key regulators of the cell cycle, triggering the transition from the growth phase (G1 phase) to the DNA replication phase (S1 phase). During cell proliferation, the complex formed by cyclin D and CDK4 / 6 phosphorylates retinoblastoma protein (Rb). Once phosphorylated, the tumor suppressor protein Rb releases its tightly bound transcription factor E2F in its unphosphorylated state. E2F activates further transcription, propelling the cell cycle through the restriction point (R point) and from G1 phase to S phase, entering the cell proliferation cycle. Therefore, inhibiting CDK4 / 6 to prevent the formation of the Cyclin D-CDK4 / 6 complex can arrest the cell cycle progression from G1 to S phase, thereby inhibiting tumor proliferation. In estrogen receptor-positive (ER+) breast cancer (BC), CDK4 / 6 overactivity is very frequent, and CDK4 / 6 is a key downstream target of ER signaling. Preclinical data indicate that dual inhibition of CDK4 / 6 and estrogen receptor (ER) signaling has a synergistic effect and can inhibit the growth of G1 phase estrogen receptor-positive (ER+) breast cancer (BC) cells.

[0006] WO2016141881 discloses a CDK4 / 6 inhibitor with the structure shown in formula (I). The compound of formula (I) has an IC50 value of less than 1 nM against CDK4 / 6 and exhibits good tumor-suppressive activity against breast cancer.

[0007]

[0008] WO2016141881 also discloses a method for preparing the compound of formula (I), the route of which is as follows:

[0009]

[0010] The preparation process of the compound of formula (I) has many drawbacks, including:

[0011] (i) The crude intermediates (2), (3), (4), (5), (6) and (7) are all oily compounds that need to be purified by silica gel column chromatography before being used in the next reaction. They are not suitable for industrial production.

[0012] (ii) The preparation processes of intermediate compounds (5), (6), (7), (8) and (9) all use metal catalysts, which result in high process costs and complex post-processing, making them unsuitable for industrial production.

[0013] (iii) When compound (8) undergoes a reduction reaction, the reduction reaction takes a long time due to the presence of a large number of N atoms that can coordinate with metals in its structure, and it is not suitable for industrial production. Summary of the Invention

[0014] The purpose of this application is to provide a new method for preparing compound (I). The reagents used in this method are economical and readily available, the intermediates generated do not require silica gel column chromatography for post-processing, 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.

[0015] On the one hand, this application provides a method for preparing a compound of formula (I), comprising:

[0016] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0017] Step 2: Compound SMA-2 reacts with hydrazine hydrate to give compound SMA-3;

[0018] Step 3: Compound SMA-3 undergoes a methylation reaction to yield compound SMA-4;

[0019] Step 4: Compound SMA-4 reacts with pinacol diboronic acid ester to give compound SMA-5;

[0020] Step 5: Compound SMA-5 reacts with compound SMA-9 to give compound SMA-6;

[0021] Step 6: Compound SMA-6 reacts with compound SMA-10 to give compound SMA-7;

[0022] Step 7: Compound SMA-7 is reacted to obtain compound (I).

[0023]

[0024] In some implementations, step 1 above is carried out in the presence of a solvent and a base.

[0025] In some embodiments, the solvent in step 1 above is selected from one or more mixed solvents selected from dichloromethane, tetrahydrofuran, dioxane, DMF, DMSO, acetonitrile, diethyl ether, isopropyl ether, methyl tertiary ether, 2-methyltetrahydrofuran, n-hexane, and n-heptane; preferably one or more mixed solvents selected from tetrahydrofuran, dioxane, and n-heptane; more preferably tetrahydrofuran.

[0026] In some embodiments, the alkali in step 1 above is selected from lithium n-butyllithium, lithium tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamino, lithium hexamethyldisilamide, sodium di(trimethylsilyl)amino, sodium hydrogen hydride, and lithium hydroxide; preferably lithium diisopropylamino, lithium n-butyllithium, and lithium hexamethyldisilamide; more preferably lithium diisopropylamino.

[0027] In some embodiments, the reaction temperature of step 1 above is -75 to -20°C; preferably -75 to -50°C; and more preferably -75 to -65°C.

[0028] In some implementations, the reaction time for step 1 above is 2 to 10 hours; preferably 2 to 6 hours; and more preferably 3 to 5 hours.

[0029] In some embodiments, the molar ratio of compound SMA-1 to compound SMA-8 in step 1 above is 1:1 to 2; preferably 1:1 to 1.5; more preferably 1:1 to 1.4. In some specific embodiments, the molar ratio of compound SMA-1 to compound SMA-8 in step 1 above is approximately 1:1.33.

[0030] In some embodiments, the molar volume ratio of compound SMA-1 to solvent in step 1 above is 1 mmol: 0.5–1.5 mL; preferably 1 mmol: 1–1.5 mL; 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 above is approximately 1 mmol: 1 mL.

[0031] In some embodiments, the molar ratio of compound SMA-1 to the base in step 1 above is 1:1 to 3; preferably 1:1.5 to 3; more preferably 1:1.5 to 2.1. In some specific embodiments, the molar ratio of compound SMA-1 to the base in step 1 above is 1:2.

[0032] In some embodiments, step 1 above includes: dissolving compounds SMA-1 and SMA-8 in a solvent to form a solution, and then adding a base to react and obtain compound SMA-2.

[0033] In some embodiments, step 1 above further includes: lowering the temperature to -75 to -20°C after the solution is formed; preferably -75 to -50°C; more preferably -75 to -65°C. In some embodiments, step 1 above further includes: adding the alkali at a temperature of -65°C.

[0034] In some implementations, step 1 above also includes reacting for 3 hours after the alkali is added.

[0035] In some embodiments, step 1 above further includes: after the reaction is complete, adding an acid to the reaction solution for treatment. In some specific embodiments, the acid is hydrochloric acid (e.g., a 1 mol / L aqueous solution of hydrochloric acid).

[0036] In some embodiments, step 1 above further includes the step of separating SMA-2 after adding acid to the reaction solution for treatment.

[0037] In some specific implementations, step 1 above is as follows: SMA-1, SMA-8, and tetrahydrofuran are stirred until dissolved and cooled to an internal temperature of -75 to -65°C. Diisopropylaminolithium is added while maintaining the internal temperature below -65°C. After the addition is complete, the reaction is carried out at -75 to -65°C for 3 hours. A 1 mol / L aqueous hydrochloric acid solution is added to the reaction mixture. After the addition is complete, the mixture is brought to room temperature, separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain compound SMA-2.

[0038] In this application, step 1 above further includes: reacting compound SMA-11 with compound SMA-12 to prepare compound SMA-8.

[0039]

[0040] In some embodiments, the steps for preparing compound SMA-8 described above are carried out in the presence of a solvent and a base.

[0041] In some embodiments, the solvent used in the above steps for 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.

[0042] In some embodiments, the base used in the above steps for 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; more preferably triethylamine.

[0043] In some embodiments, the reaction temperature for the above-described steps for preparing compound SMA-8 is 0–30°C; preferably 5–25°C; more preferably 15–25°C. In some specific embodiments, the reaction temperature for the above-described steps for preparing compound SMA-8 is approximately 25°C.

[0044] In some embodiments, the reaction time for the above-described steps for preparing compound SMA-8 is 0.5 to 5 hours; preferably 0.5 to 2 hours; more preferably 1 to 2 hours.

[0045] In some embodiments, in the steps for preparing compound SMA-8 described above, the molar ratio of compound SMA-11 to compound SMA-12 is 1:1 to 2; preferably 1:1 to 1.5; 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.

[0046] In some embodiments, in the steps for preparing compound SMA-8 described above, the molar volume ratio of compound SMA-11 to the solvent is 1 mmol: 0.2–2 mL; preferably 1 mmol: 0.5–2 mL; more preferably 1 mmol: 0.5–1 mL. In some specific embodiments, the molar volume ratio of compound SMA-11 to the solvent is approximately 1 mmol: 0.5 mL.

[0047] In some embodiments, in the steps for preparing compound SMA-8 described above, the molar ratio of compound SMA-11 to the base is 1:1 to 3; preferably 1:1.5 to 3; more preferably 1:1.5 to 2. In some specific embodiments, the molar ratio of compound SMA-11 to the base is approximately 1:2.

[0048] In some embodiments, in the steps for preparing compound SMA-8 described above, compound SMA-12 is first mixed with a solvent (e.g., mixed at a temperature of -5 to 5°C), then a base is added (e.g., the base is added at a temperature below 5°C), followed by the addition of...

[0049] SMA-11 (for example, SMA-11 is added when the temperature is below 5°C).

[0050] In some embodiments, the steps for preparing compound SMA-8 are as follows: SMA-12 is dissolved in dichloromethane, the temperature is maintained at -5 to 5°C, triethylamine is added, and the temperature is maintained below 5°C; after the addition is complete, the temperature is maintained below 5°C and then...

[0051] SMA-11 was added, and the reaction was carried out at room temperature for 1 hour.

[0052] In some embodiments, the steps for preparing compound SMA-8 described above further include a step of treating the compound with an alkali (e.g., sodium bicarbonate) after the reaction is complete.

[0053] In this application, the compound SMA-8 in step 1 above can also be purchased commercially.

[0054] In some implementations, step 2 above is performed in the presence of a solvent.

[0055] In some embodiments, the solvent in step 2 above 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; preferably DMF and ethylene glycol; more preferably ethylene glycol.

[0056] In some implementations, step 2 above also includes a step of removing water during the reaction.

[0057] In some implementations, step 2 above is: after the compound SMA-2 reacts with hydrazine hydrate for a period of time, the water is removed, and the reaction continues.

[0058] In some embodiments, the reaction temperature in step 2 above is 100–200°C; preferably 150–200°C.

[0059] In some embodiments, step 2 above comprises: reacting compound SMA-2 with hydrazine hydrate first at a temperature of 180–200°C or under reflux conditions, and then reacting at a temperature of 150°C. Specifically, a water removal step is performed between the two reaction stages. In some embodiments, the reaction time for step 2 above is 2–15 hours; preferably 5–12 hours; more preferably 10–12 hours.

[0060] In some embodiments, step 2 above involves reacting compound SMA-2 with hydrazine hydrate first at 180–200°C or under reflux for 2 hours, followed by a reaction at 150°C for 10 hours. Specifically, a step of removing water occurs between the two reaction stages.

[0061] In some embodiments, the molar ratio of compound SMA-2 to hydrazine hydrate in step 2 above is 1:1 to 3; preferably 1:1.5 to 3; more preferably 1:1.5 to 2.

[0062] In some embodiments, the molar volume ratio of compound SMA-2 to solvent in step 2 above is 1 mmol: 0.5 to 1.5 mL; preferably 1 mmol: 1 to 1.5 mL; more preferably 1 mmol: 1 to 1.2 mL.

[0063] In some embodiments, step 2 above is as follows: SMA-2 and hydrazine hydrate are refluxed in the presence of ethylene glycol for 2 hours to remove water from the reaction system, and then reacted at 150°C for 10 hours to obtain compound SMA-3.

[0064] In some embodiments, step 2 above further includes adding water to the reaction system after the reaction is complete to precipitate compound SMA-3. Further, it also includes a step of pulping with purified water.

[0065] In some implementations, step 3 above is performed in the presence of a methylating agent and a solvent.

[0066] In some embodiments, the methylating agent in step 3 above is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, tetramethylammonium fluoride, trimethyl phosphate, trimethyloxonium tetrafluoroboric acid, and 1-methyl-3-p-tolyltriazine; preferably iodomethane and trimethyloxonium tetrafluoroboric acid; more preferably trimethyloxonium tetrafluoroboric acid.

[0067] In some embodiments, the solvent in step 3 above is selected from one or a mixture of two or more solvents selected from ethyl acetate, dichloromethane, and acetone; preferably, it is one or a mixture of two or more solvents selected from ethyl acetate and dichloromethane. In some specific embodiments, ethyl acetate is used first, followed by dichloromethane as the solvent in step 3 above. In some specific embodiments, the solvent in step 3 above is ethyl acetate.

[0068] In some implementations, step 3 above can also be carried out in the presence of a methylating agent, a base, and a solvent.

[0069] In some embodiments, the alkali in step 3 above 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.

[0070] In some embodiments, the reaction temperature in step 3 above is controlled at 10–30°C; preferably 20–30°C; and more preferably 25–30°C.

[0071] In some embodiments, the reaction time for step 3 above is 5 to 12 hours; preferably 8 to 12 hours; more preferably 8 to 10 hours. In some specific embodiments, the reaction time for step 3 above is approximately 8 hours.

[0072] In some embodiments, step 3 above is: reacting compound SMA-3 with trimethyloxonium tetrafluoroboric acid to obtain a tetrafluoroboronium salt of compound SMA-4, and reacting the tetrafluoroboronium salt of compound SMA-4 to obtain compound

[0073] SMA-4.

[0074] In some embodiments, the step of reacting the tetrafluoroborate salt of the above-mentioned compound SMA-4 to obtain compound SMA-4 can be carried out in the presence of a base (e.g., sodium bicarbonate).

[0075] In some embodiments, the preparation of the tetrafluoroborate onium salt of the above-mentioned compound SMA-4 is carried out in the presence of a solvent selected from ethyl acetate and acetone; preferably ethyl acetate.

[0076] In some embodiments, the preparation of the tetrafluoroborate onium salt of the above-mentioned compound SMA-4 is carried out in the presence of a solvent selected from ethyl acetate and acetone; preferably ethyl acetate.

[0077] In some embodiments, the step of reacting the tetrafluoroborate salt of the above-mentioned 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 more preferably ethyl acetate.

[0078] In some embodiments, step 3 above is: reacting compound SMA-3 with trimethyloxonium tetrafluoroboric acid in the presence of ethyl acetate to obtain the onium tetrafluoroborate salt of compound SMA-4, and reacting the onium tetrafluoroborate salt of compound SMA-4 in the presence of dichloromethane and a base to obtain compound SMA-4.

[0079] In some embodiments, step 3 above is as follows: compound SMA-3 reacts with trimethyloxonium tetrafluoroboric acid in the presence of ethyl acetate at a temperature of 25-30°C to obtain the onium tetrafluoroborate salt of compound SMA-4; the onium tetrafluoroborate salt of compound SMA-4 is separated; and the onium tetrafluoroborate salt of compound SMA-4 is reacted with sodium bicarbonate in the presence of dichloromethane and water to obtain compound SMA-4.

[0080] In some embodiments, the molar ratio of compound SMA-3 to the methylating agent in step 3 above is 1:1 to 3; preferably 1:1 to 2; more preferably 1:1 to 1.2.

[0081] In some embodiments, the molar ratio of compound SMA-3 to base in step 3 above is 1:1 to 5; preferably 1:2 to 4; and more preferably 1:2.5 to 3.5.

[0082] In some implementations, step 4 above is carried out in the presence of a catalyst, a base, and a solvent.

[0083] In some embodiments, the catalyst in step 4 above 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(triphenylphosphino)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, or tris(dibenzylacetone)palladium; preferably bis(triphenylphosphino)palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; more preferably 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride.

[0084] In some embodiments, the alkali in step 4 above 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.

[0085] In some embodiments, the solvent in step 4 above is selected from one or more mixed solvents of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile, and water; preferably tetrahydrofuran and dioxane; more preferably dioxane.

[0086] In some embodiments, the reaction temperature of step 4 above is 80–120°C; preferably 85–105°C; more preferably 90–105°C. In some specific embodiments, the reaction temperature of step 4 above is 90–95°C.

[0087] In some embodiments, the reaction time for step 4 is 5 to 15 hours; preferably 8 to 12 hours; more preferably 8 to 10 hours. In some specific embodiments, the reaction time for step 4 is approximately 9 hours.

[0088] In some embodiments, the molar ratio of compound SMA-4 to pinacol diboronate in step 4 above is 1:1 to 3; preferably 1:1 to 2; more preferably 1:1 to 1.5.

[0089] In some embodiments, the molar ratio of compound SMA-4 to catalyst in step 4 above is 1:0.001 to 0.01; preferably 1:0.002 to 0.008; and more preferably 1:0.004 to 0.006.

[0090] In some embodiments, the molar ratio of compound SMA-4 to base in step 4 above is 1:1 to 3; preferably 1:1 to 2; more preferably 1:1.5 to 2.

[0091] In some embodiments, the molar volume ratio of compound SMA-4 to solvent in step 4 above is 1 mmol: 1-2 mL; preferably 1 mmol: 1-1.5 mL; more preferably 1 mmol: 1.2-1.5 mL.

[0092] In some embodiments, step 4 above is: reacting compound SMA-4 with pinacol diborate in the presence of 1,4-dioxane, potassium acetate and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride to obtain compound SMA-5.

[0093] In some embodiments, step 4 above is: reacting compound SMA-4 with pinacol diborate in the presence of 1,4-dioxane, potassium acetate and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride at a reaction temperature of 90-95°C for 9 hours to obtain compound SMA-5.

[0094] In some implementations, step 5 above is carried out in the presence of a catalyst, a base, and a solvent.

[0095] In some embodiments, the catalyst in step 5 above 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(triphenylphosphino)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, or tris(dibenzylacetone)palladium; preferably bis(triphenylphosphino)palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; more preferably 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride.

[0096] In some embodiments, the alkali in step 5 above 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.

[0097] In some embodiments, the solvent in step 5 above is selected from one or more mixed solvents of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile, and water; preferably dioxane and toluene; more preferably dioxane.

[0098] In some embodiments, the reaction temperature of step 5 above is 80–120°C; preferably 85–105°C; and more preferably 90–105°C.

[0099] In some implementations, the reaction time for step 5 above is 5 to 15 hours; preferably 8 to 12 hours; and more preferably 10 to 12 hours.

[0100] In some embodiments, the molar ratio of compound SMA-5 to compound SMA-9 in step 5 above is 1:1 to 2; preferably 1:1 to 1.5; more preferably 1:1 to 1.2.

[0101] In some embodiments, the molar ratio of compound SMA-5 to catalyst in step 5 above is 1:0.005 to 0.05; preferably 1:0.01 to 0.05; and more preferably 1:0.01 to 0.03.

[0102] In some embodiments, the molar ratio of compound SMA-5 to base in step 5 above is 1:1 to 3; preferably 1:1 to 2; more preferably 1:1.5 to 2.

[0103] In some embodiments, the molar volume ratio of compound SMA-5 to solvent in step 5 above is 1 mmol: 0.1 to 2 mL; preferably 1 mmol: 0.2 to 1 mL; more preferably 1 mmol: 0.2 to 0.5 mL.

[0104] In some embodiments, step 5 above is: reacting compound SMA-5 and compound SMA-9 in the presence of potassium carbonate, water and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride at a temperature of 90-95°C to obtain compound SMA-6.

[0105] In some embodiments, step 5 above further includes a step of treating the reaction with a mixed solution of ethanol and water after the reaction is complete. It further includes a step of treating the separated solid by adding it to a mixed system of water and dichloromethane. It further includes a step of separating the organic phase after treatment and treating the organic phase with anhydrous sodium sulfate and activated carbon.

[0106] In some embodiments, step 5 above further includes purifying compound SMA-6 with ethyl acetate.

[0107] In some implementations, step 6 above is carried out in the presence of a catalyst, a base, and a solvent.

[0108] In some embodiments, the catalyst in step 6 above 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(diphenylphosphine)ferrocene palladium dichloride, and tris(dibenzylacetone) dipapadium; preferably palladium acetate and tris(dibenzylacetone) dipapadium; more preferably palladium acetate.

[0109] In some embodiments, the catalyst in step 6 above is selected from palladium acetate and tris(dibenzylacetone)dipalladium, wherein the catalyst is used in the presence of a ligand selected from 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-biscyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, 1,1'-bidinaphthol, and 2,2'-bis-(diphenylphosphino)-1,1'-binaphthol; preferably 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene and 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl; more preferably 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0110] In some embodiments, step 6 above is carried out in the presence of palladium acetate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, a base, and a solvent.

[0111] In some embodiments, the alkali in step 6 above 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.

[0112] In some embodiments, the solvent in step 6 above is selected from one or more mixed solvents of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile, and water; preferably tetrahydrofuran and dioxane; more preferably dioxane.

[0113] In some embodiments, the reaction temperature of step 6 above is 80–150°C; preferably 80–120°C; more preferably 100–120°C. In some specific embodiments, the reaction temperature of step 6 above is approximately 110°C.

[0114] In some embodiments, the reaction time for step 6 is 3 to 10 hours; preferably 3 to 8 hours; more preferably 4 to 6 hours. In some specific embodiments, the reaction time for step 6 is approximately 5 hours.

[0115] In some embodiments, the molar ratio of compound SMA-6 to compound SMA-10 in step 6 above is 1:1 to 2; preferably 1:1 to 1.5; more preferably 1:1 to 1.2.

[0116] In some embodiments, the molar ratio of compound SMA-6 to catalyst in step 6 above is 1:0.01 to 0.1; preferably 1:0.02 to 0.06; more preferably 1:0.02 to 0.04.

[0117] In some embodiments, the molar ratio of compound SMA-6 to the ligand in step 6 above is 1:0.01 to 0.1; preferably 1:0.02 to 0.06; more preferably 1:0.04 to 0.06.

[0118] In some embodiments, the molar ratio of compound SMA-6 to base in step 6 above is 1:1 to 3; preferably 1:1.5 to 3; more preferably 1:1.5 to 2.

[0119] In some embodiments, the molar volume ratio of compound SMA-6 to solvent in step 6 above is 1 mmol: 1-8 mL; preferably 1 mmol: 2-6 mL; more preferably 1 mmol: 3-4 mL.

[0120] In some embodiments, step 6 above is: compound SMA-6 and compound SMA-10 are reacted at 110°C in the presence of cesium carbonate, 1,4-dioxane, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and palladium acetate to obtain compound SMA-7.

[0121] In some embodiments, step 6 above further includes adding dichloromethane to the reaction system after the reaction is complete. It further includes adding sodium sulfate and mercaptosilica gel, stirring, and filtering.

[0122] In some embodiments, step 6 above further includes the step of pulping compound SMA-7 with ethyl acetate.

[0123] In this application, compound SMA-10 can be prepared by referring to the method disclosed in specification WO2018045993.

[0124] In this application, compound SMA-10 is also commercially available.

[0125] In some implementations, step 7 is carried out in the presence of acid and solvent.

[0126] 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.

[0127] In some specific embodiments, the acid in step 7 is selected from hydrogen chloride, and the solvent in step 7 is selected from methanol. After removing the protecting group from compound SMA-7 in step 7, the hydrochloride salt of compound (I) is first obtained; further, the hydrochloride salt of compound (I) is neutralized with a base to obtain compound (I). In some embodiments, the base neutralized with the hydrochloride salt of compound (I) is selected from aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, or aqueous potassium carbonate solution; preferably, aqueous sodium hydroxide solution.

[0128] In this application, the compound SMA-7 undergoes a deprotection reaction to obtain compound (I), which can also be prepared by referring to the method disclosed in Example 3 of WO201614188.

[0129] This application also provides a method for preparing the intermediate SMA-6, comprising:

[0130] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0131] Step 2: Compound SMA-2 reacts with hydrazine hydrate to give compound SMA-3;

[0132] Step 3: Compound SMA-3 undergoes a methylation reaction to yield compound SMA-4;

[0133] Step 4: Compound SMA-4 reacts with pinacol diboronic acid ester to give compound SMA-5;

[0134] Step 5: Compound SMA-5 reacts with compound SMA-9 to obtain compound SMA-6.

[0135]

[0136] In some embodiments, the reaction conditions of steps 1, 2, 3, 4 and 5 in the preparation method of the above intermediate SMA-6 are as described in steps 1, 2, 3, 4 and 5 in the preparation method of compound of formula (I) in this application.

[0137] This application also provides a method for preparing intermediate SMA-6 and its use in the preparation of compound (I).

[0138] This application also provides a method for preparing the intermediate SMA-3, comprising:

[0139] Step 1: Compound SMA-1 reacts with compound SMA-8 to obtain compound SMA-2;

[0140] Step 2: Compound SMA-2 reacts with hydrazine hydrate to obtain compound SMA-3.

[0141]

[0142] In some embodiments, the reaction conditions for steps 1 and 2 in the preparation method of the above intermediate SMA-3 are as described in steps 1 and 2 in the preparation method of compound of formula (I) in this application.

[0143] This application also provides a method for preparing the above-mentioned intermediate SMA-3 and its use in the preparation of compound (I).

[0144] This application also provides a method for preparing the intermediate SMA-4, comprising:

[0145] Compound SMA-3 undergoes a methylation reaction to yield compound SMA-4.

[0146]

[0147] In some embodiments, the reaction conditions in the preparation of the intermediate SMA-4 are as described in step 3 of the preparation method of compound (I) in this application.

[0148] In one specific embodiment, the preparation method of intermediate SMA-4 includes: reacting compound SMA-3 with trimethyloxonium tetrafluoroboric acid to generate onium salt intermediate compound SMA-3' (onium tetrafluoroborate salt of compound SMA-4), and further hydrolyzing onium salt intermediate compound SMA-3' to obtain compound SMA-4.

[0149]

[0150] In some embodiments, the formation of the above-mentioned onium salt intermediate compound SMA-3' is carried out in the presence of a solvent.

[0151] In some embodiments, the solvent for generating the above-mentioned onium salt intermediate compound SMA-3' is selected from ethyl acetate and acetone; ethyl acetate is preferred.

[0152] In some embodiments, the reaction temperature for generating the above-mentioned onium salt intermediate compound SMA-3' is controlled at 10–30°C; preferably 20–30°C; and more preferably 25–30°C.

[0153] In some embodiments, the reaction time for generating the above-mentioned onium salt intermediate compound SMA-3' is 5 to 12 hours; preferably 8 to 12 hours; more preferably 8 to 10 hours.

[0154] In some embodiments, the molar ratio of compound SMA-3, which is formed from the above-mentioned onium salt intermediate compound SMA-3', to trimethyloxonium tetrafluoroboric acid is 1:1 to 3; preferably 1:1 to 2; and more preferably 1:1 to 1.2.

[0155] In some embodiments, the molar volume ratio of compound SMA-3 in the formation of the above-mentioned onium salt intermediate compound SMA-3' to the solvent is 1 mmol: 1-5 mL; preferably 1 mmol: 2-4 mL; more preferably 1 mmol: 2-3 mL.

[0156] 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.

[0157] In some embodiments, the base from the hydrolysis of the above-mentioned onium salt intermediate compound SMA-3' is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide; sodium bicarbonate and sodium hydroxide are preferred; sodium bicarbonate is even more preferred.

[0158] In some embodiments, the base obtained by hydrolyzing the above-mentioned onium salt intermediate compound SMA-3' is its aqueous solution.

[0159] In some embodiments, the solvent in which the above-mentioned onium salt intermediate compound SMA-3' is hydrolyzed is the same as the solvent in which the above-mentioned onium salt intermediate is generated.

[0160] In some embodiments, the solvent for hydrolyzing the above-mentioned onium salt intermediate compound SMA-3' is selected from dichloromethane and ethyl acetate; dichloromethane is preferred.

[0161] In some implementations, the solvents required for the formation and hydrolysis of the aforementioned onium salt intermediate compound SMA-3' may be the same or different.

[0162] In some embodiments, the molar ratio of the above-mentioned onium salt intermediate compound SMA-3' to the base is 1:1 to 5; preferably 1:1 to 3; more preferably 1:2 to 3.

[0163] In some embodiments, the hydrolysis reaction time of the above-mentioned onium salt intermediate compound SMA-3' is 0.5 to 3 hours; preferably 0.5 to 1 hour.

[0164] This application also provides the use of the method for preparing the above intermediate SMA-4 in the preparation of compound (I).

[0165] The preparation of the compound of formula (I) may also include the purification of the crude product.

[0166] Compound SMA-1, hydrazine hydrate, pinacol diboronate, and compound SMA-9 used in this application are all commercially available.

[0167] The method for preparing the compound of formula (I) and its intermediates provided in this application has the following advantages:

[0168] (i) No silica gel column chromatography was used in the post-processing of the intermediates prepared in this application. The post-processing operation is simple, economical and readily available.

[0169] (ii) The metal catalyst used in the preparation of the compound of formula (I) of this application is less than that of the prior art in terms of both the number of reaction steps and the amount used, making it more economical, and the metal residue in the final product is also correspondingly less.

[0170] (iii) Compared with the prior art, the preparation of compound (I) of this application reduces the allyl reduction step, greatly shortens the reaction time, and avoids the use of rhodium catalyst, making it more economical and environmentally friendly.

[0171] (iv) The starting materials and reagents for the preparation of the compound of formula (I) of this application are inexpensive and readily available, the overall reaction steps are greatly shortened, the reaction time is shortened, the overall yield is increased, and the purity of the key intermediates and the final product is high, making it very suitable for industrial production.

[0172] In this application, LDA refers to lithium diisopropylamino; 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 diborate; Pd(dppf)Cl2 refers to 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride; TLC refers to thin-layer chromatography; HPLC refers to high-performance liquid chromatography. Detailed Implementation

[0173] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement this application. They should not be considered as limitations on this application, but merely as exemplary illustrations and typical representatives.

[0174] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0175] All solvents used in this application are commercially available and can be used without further purification.

[0176] Preparation of compound SMA-8

[0177]

[0178] N,O-dimethylhydroxylamine hydrochloride (SMA-12) (5.0 kg) was added to a 100 L reactor, followed by dichloromethane (26 L) and stirring to dissolve. The mixture was cooled to an internal temperature of -5 to 5 °C, and triethylamine (10.4 kg) was slowly added dropwise, maintaining the internal temperature below 5 °C during the addition. After the addition was complete, isobutyryl chloride (SMA-11) (5.46 kg) was added dropwise while maintaining the internal temperature below 5 °C. The reaction was stopped, and the mixture was stirred at room temperature for 1 hour. TLC analysis showed that the isobutyryl chloride reacted completely. The reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (77 L), and the mixture was separated. The organic phase was washed successively with 1 mol / L hydrochloric acid (26 L) and 10% sodium chloride aqueous solution (26 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.5 kg of compound SMA-8, with a yield of 81.8%.

[0179] Preparation of compound (I)

[0180]

[0181] Preparation of compound SMA-2

[0182] Add 4 kg of p-fluorobromobenzene (SMA-1), 4.0 kg of N,O-dimethylisobutyramide (SMA-8), and 23.2 L of tetrahydrofuran to a 100 L stainless steel reactor. Stir until dissolved and cool to an internal temperature of -75 to -65 °C. Slowly add LDA (2 mol / L, 23.2 L) dropwise while maintaining the internal temperature below -65 °C. After addition, stir and react for 3 hours while maintaining the internal temperature of -75 to -65 °C. Add 46 L of 1 mol / L hydrochloric acid aqueous solution dropwise to the reaction solution. After addition, slowly raise the temperature to room temperature, separate the layers, extract the aqueous phase with 15 L of ethyl acetate, combine the organic phases, wash with water (10 L × 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 6.18 kg of compound SMA-2, with a yield of 85.7%.

[0183] Preparation of compound SMA-3

[0184] 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. Water was removed from the reaction system, and the reaction was continued at 150 °C for 10 hours. The mixture was slowly cooled to room temperature, and 23 L of purified water was added. Crystallization was carried out by stirring for 1 hour. The mixture was filtered, and the filter cake was mixed with 25 L of purified water to form a slurry. After filtration, the slurry was dried at 50 °C with forced air to obtain 3.2 kg of compound SMA-3, with a yield of 70%.

[0185] Preparation of compound SMA-4

[0186] Compound SMA-3 (3 kg) and ethyl acetate (30 L) were added to a 50 L reactor. Trimethyloxonium tetrafluoroboric acid (2.06 kg) was added under nitrogen protection. After the addition was complete, the mixture was stirred at 25-30 °C for 8 hours. The mixture was then filtered, and the filter cake was slurried with 40 L of n-hexane for 3 hours. The mixture was then filtered again and dried by forced air to obtain 3.3 kg of onium tetrafluoroborate salt of compound SMA-4 (SMA-3'), with a yield of 77.1%.

[0187] Add 135g of the tetrafluoroborate salt of the above compound SMA-4 to a 5L beaker, then add 1L of saturated NaHCO3 solution and 1L of dichloromethane, stir for 0.5 hours, separate the contents, wash once with 500mL of saturated NaCl solution, separate the contents again, and concentrate the organic phase to dryness to obtain compound SMA-4 for later use.

[0188] Preparation of compound SMA-5

[0189] The compound SMA-4 obtained above, 1,4-dioxane (500 mL), pinacol diborate (151 g), and potassium acetate (78 g) were added to a 1 L four-necked flask. The mixture was degassed and purged three times with nitrogen. Under nitrogen protection, Pd(dppf)Cl2CH2Cl2 (1.5 g) was added. After the addition was complete, the mixture was heated to an internal temperature of 90–95 °C and stirred for 9 hours. The mixture was then cooled to room temperature and filtered. It was washed with 1,4-dioxane (50 mL) to obtain a filtrate containing compound SMA-5 for later use.

[0190] Preparation of compound SMA-6

[0191] The filtrate containing compound SMA-5 was transferred to a 1L four-necked flask, and 68g of 2,4-dichloro-5-fluoropyrimidine (SMA-9) and 111g of potassium carbonate were added sequentially. 100mL of purified water was added with stirring, the mixture was degassed, and purged three times with nitrogen. Pd(dppf)Cl2 was then added under nitrogen protection. After adding CH2Cl2 (3.3g), the mixture was heated to an internal temperature of 90-95℃ and stirred for 12 hours. The mixture was then cooled to room temperature and concentrated. It was then slurried in 500mL of an aqueous ethanol solution (ethanol / water = 1 / 1) for 1 hour, filtered, and the solid was added to a mixture of 500mL of water and 300mL of dichloromethane. The mixture was stirred to dissolve, and the liquid phase was separated. The aqueous phase was extracted with dichloromethane (100mL*2). The organic phases were combined, and the mixture was dehydrated and decolorized with anhydrous Na2SO4 and 3% activated carbon for 0.5 hours. The mixture was filtered, concentrated to dryness, and 75g of crude product was obtained. The crude product was slurried in ethyl acetate (200mL) for 0.5 hours, filtered, and dried to obtain 60g of pure SMA-6 compound with a purity of 99.1% and a yield of 50.1%.

[0192] Preparation of compound SMA-7

[0193] 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 sequentially added to a 50 L reactor. Under nitrogen protection, the mixture was stirred at 110 °C for 5 hours. After cooling, 20 L of dichloromethane was added to the reaction mixture and stirred for 30 minutes. The mixture was filtered through diatomaceous earth, washed twice with water, and then filtered with sodium sulfate and mercaptosilica (5%). The filtrate was then filtered with 5% mercaptosilica and stirred again. The filtrate was concentrated to dryness, and ethyl acetate (17 L) was added and stirred for 2 hours. The mixture was then filtered and dried to obtain compound SMA-7, which was directly used in the next reaction.

[0194] Preparation of compound (I)

[0195] 1.9 kg of hydrogen chloride gas was bubbled into a 12.5 L methanol solution to obtain a 4 M hydrogen chloride / methanol solution. 12.5 L of methanol and compound SMA-7 were added sequentially to a reaction vessel at 20 °C to obtain a suspension. Then, 12.5 L of the 4 M hydrogen chloride / methanol solution was added to a 50 L reaction vessel, and the system temperature was raised to 50 °C. After 10 minutes, a solid 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. The filter cake was washed with 5 L of methanol and dried in a vacuum oven at 50 °C for 42 hours to obtain the crude hydrochloride salt of compound (I), which was directly used for the next reaction.

[0196] At 20°C, 2.60 kg of crude hydrochloride of compound (I) and 7.8 L of ethanol were sequentially added to a 50 L reactor. The resulting turbid liquid was heated to 75°C, and 12.4 L of 5% sodium hydroxide aqueous solution was added dropwise to the reactor to adjust the pH to approximately 11. The reaction system was cooled to 68°C, and solids began to precipitate after about 5 minutes. 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 × 2 of water. The resulting filter cake was dried in a vacuum oven at 60°C for 48 hours to obtain 1.9 kg of compound (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: reacting compound SMA-1 with compound SMA-8 to obtain compound SMA-2; Step 2: reacting compound SMA-2 with hydrazine hydrate to obtain compound SMA-3; Step 3: methylating compound SMA-3 to obtain compound SMA-4; Step 4: reacting compound SMA-4 with pinacol diboron to obtain compound SMA-5; Step 5: reacting compound SMA-5 with compound SMA-9 to obtain compound SMA-6; Step 6: reacting compound SMA-6 with compound SMA-10 to obtain compound SMA-7; Step 7: reacting compound SMA-7 to obtain the compound of formula (I); 2. A process for the preparation of a compound of formula (I) as claimed in claim 1, wherein, Step 1 is carried out in the presence of a solvent and a base; the solvent is selected from one or more than two mixed solvents selected from dichloromethane, tetrahydrofuran, dioxane, DMF, DMSO, acetonitrile, diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-hexane and n-heptane; preferably one or more than two mixed solvents selected from tetrahydrofuran, dioxane and n-heptane; further preferably tetrahydrofuran; the base is selected from n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilylamide, sodium bis(trimethylsilyl)amide, sodium hydride and lithium hydroxide; preferably lithium diisopropylamide, n-butyllithium and lithium hexamethyldisilylamide; further preferably lithium diisopropylamide.

3. A process for the preparation of a compound of formula (I) as claimed in claim 2, wherein, The molar ratio of compound SMA-1 to compound SMA-8 is 1:1-2; preferably 1:1-1.5; further preferably 1:1-1.

4.

4. A process for the preparation of a compound of formula (I) as claimed in claim 2, wherein, The molar volume ratio of compound SMA-1 to solvent is 1 mmol: 0.5-1.5 mL; preferably 1 mmol: 1-1.5 mL; further preferably 1 mmol: 1-1.2 mL.

5. A process for the preparation of a compound of formula (I) as claimed in 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, mesitylene, diethylene glycol dimethyl ether and N-methylpyrrolidone; preferably DMF and ethylene glycol; further preferably ethylene glycol.

6. A process for the preparation of a compound of formula (I) as claimed in claim 1, wherein, Step 3 is carried out in the presence of a methylating agent and a solvent; the methylating agent is selected from methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl triflate, tetramethylammonium fluoride, trimethyl phosphate, trimethyloxosulfonium tetrafluoroborate and 1-methyl-3-p-tolyltriazene; preferably methyl iodide and trimethyloxosulfonium tetrafluoroborate; further preferably trimethyloxosulfonium tetrafluoroborate; the solvent is selected from one or more than two mixed solvents selected from ethyl acetate, dichloromethane and acetone; preferably one or more than two mixed solvents selected from ethyl acetate and dichloromethane.

7. A process for the preparation of a compound of formula (I) as claimed in 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(cyanophenyl) palladium dichloride, 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride or tris(dibenzylideneacetone) dipalladium; preferably bis(triphenylphosphine) palladium dichloride or 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride; further preferably 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride; 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; preferably potassium acetate or cesium carbonate; further preferably potassium acetate; the solvent is selected from one or more than one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water; preferably tetrahydrofuran and dioxane; further preferably dioxane. 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(cyanophenyl) palladium dichloride, 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride or tris(dibenzylideneacetone) dipalladium; preferably bis(triphenylphosphine) palladium dichloride or 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride; further preferably 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride; 8. A process for the preparation of a compound of formula (I) as claimed in claim 1, wherein, 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; preferably cesium carbonate or potassium carbonate; further preferably potassium carbonate; the solvent is selected from one or more than one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water; preferably dioxane and toluene; further preferably dioxane. 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(cyanophenyl) palladium dichloride, 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride and tris(dibenzylideneacetone) dipalladium; preferably palladium acetate and tris(dibenzylideneacetone) dipalladium; further preferably palladium acetate; 9. A process for the preparation of a compound of formula (I) as claimed in claim 1, wherein, 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; preferably sodium carbonate, potassium carbonate and cesium carbonate; further preferably cesium carbonate; the solvent is selected from one or more than one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water; preferably methanol and ethanol; further preferably methanol. The solvent is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water, and a mixed solvent of two or more thereof; preferably tetrahydrofuran and dioxane; further preferably dioxane.

10. A method for preparing intermediate SMA-6, comprising: Step 1: reacting compound SMA-1 with compound SMA-8 to obtain compound SMA-2; Step 2: reacting compound SMA-2 with hydrazine hydrate to obtain compound SMA-3; Step 3: methylating compound SMA-3 to obtain compound SMA-4; Step 4: reacting compound SMA-4 with pinacol diborane to obtain compound SMA-5; Step 5: reacting compound SMA-5 with compound SMA-9 to obtain compound SMA-6; Step 6: reacting compound SMA-6 with compound SMA-10 to obtain compound SMA-7.

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