A process for the preparation of quinolinone derivatives

Abstract

The present application belongs to the field of medicine synthesis, and relates to a preparation method of quinolinone derivatives, in particular to a preparation method of a compound of formula I, an intermediate compound of formula D and the use of the intermediate compound of formula D for preparing the compound of formula I.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine synthesis, and relates to a preparation method of a quinolinone derivative, in particular to a preparation method of a compound of formula I, an intermediate compound of formula D and the use of the intermediate compound of formula D for preparing the compound of formula I. BACKGROUND

[0002] Spleen tyrosine kinase (Syk) is an intracellular tyrosine protein kinase, which belongs to the member of ZAP70 protein kinase family. Syk plays a key role in the early development of B cells, lymphocyte individual development and the function of mature B cells. In this process, it participates in various signal transduction pathways and can function without the phosphorylation of Src kinase. In addition to being expressed in hematopoietic stem cells, Syk is also expressed in non-hematopoietic cells such as epithelial cells, hepatocytes, fibroblasts, nerve cells and mammary tissue and has various functions.

[0003] Syk PTK dysfunction exists in many human diseases, such as allergic reactions, asthma, inflammation and autoimmune diseases. Numerous studies have shown that Syk is an important mediator in acute or chronic inflammation. The activation of Syk exists in several common B-cell malignancies, such as follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Antigen-independent phosphorylation of Syk can be detected in these diseases. Researchers found that inhibiting Syk in follicular lymphoma and diffuse large B-cell lymphoma cells can reduce the phosphorylation level of downstream signaling molecules, thereby inhibiting the proliferation and survival of tumor cells. In addition, translocation of Syk is found in myelodysplastic syndrome and peripheral T-cell lymphoma, further indicating that this kinase can act as an oncogene. Therefore, the inhibition of Syk activity can be used to treat specific types of cancer including B-cell lymphoma and leukemia.

[0004] WO2018228475 discloses a Syk inhibitor as shown in the following formula I:

[0005]

[0006] WO2018228475 Example 9 discloses a preparation method of the compound of formula I, but the preparation method route is long, the yield is low, and silica gel column chromatography is used in the multi-step reaction, which is not suitable for industrial production. Therefore, it is necessary to find a more simple and convenient synthesis method of the compound of formula I with higher yield and more suitable for industrial production. SUMMARY

[0007] In one aspect, the present application provides a method for preparing a compound of Formula D, comprising: reacting a compound of Formula B with a compound of Formula C to obtain a compound of Formula D.

[0008]

[0009] In some embodiments of the present application, the above method for preparing a compound of Formula D, wherein the reaction of the compound of Formula B with the compound of Formula C is carried out in the presence of a base and a dehydrating agent.

[0010] In some embodiments of the present application, the above method for preparing a compound of Formula D, the base is selected from an organic base or an inorganic base; the inorganic base is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably sodium acetate, potassium acetate, sodium methoxide or sodium ethoxide, more preferably sodium acetate or potassium acetate, further preferably sodium acetate; the organic base is selected from triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine, preferably N,N-diisopropylethylamine, triethylamine or N,N-dimethylaminopyridine, more preferably N,N-diisopropylethylamine or triethylamine, further preferably N,N-diisopropylethylamine.

[0011] In some embodiments of the present application, the above method for preparing a compound of Formula D, the dehydrating agent includes, but is not limited to, acetic anhydride, propionic anhydride, phthalic anhydride or butenedioic anhydride, preferably acetic anhydride or phthalic anhydride, more preferably acetic anhydride.

[0012] In some embodiments of the present application, the above method for preparing a compound of Formula D, the reaction can be carried out in an organic solvent or in the absence of a solvent; the organic solvent is selected from one or more mixed solvents of ethylene glycol, ethylene glycol monomethyl ether, butanol, octanol, octyl acetate, dioxane, DMF or DMSO, preferably one or more mixed solvents of dioxane, DMF or DMSO, more preferably DMF.

[0013] In some embodiments of the present application, the above method for preparing a compound of Formula D, the molar ratio of the compound of Formula B to the compound of Formula C is 1:1-7, preferably 1:1-5, more preferably 1:1-3. In a specific embodiment of the present application, the molar ratio of the compound of Formula B to the compound of Formula C is 1:1, 1:2 or 1:3. In a more specific embodiment of the present application, the molar ratio of the compound of Formula B to the compound of Formula C is 1:3.

[0014] In some embodiments of the application, the process for preparing the compound of formula D as described above, the molar ratio of the compound of formula B to the base is 1:1-5, preferably 1:1-3, more preferably 1:1-2. In a particular embodiment of the application, the molar ratio of the compound of formula B to the base is 1:1, 1:1.5 or 1:2. In a more particular embodiment of the application, the molar ratio of the compound of formula B to the base is 1:2.

[0015] In some embodiments of the application, the process for preparing the compound of formula D as described above, the molar ratio of the compound of formula B to the dehydrating agent is 1:1-20, preferably 1:5-15, more preferably 1:10-15. In a particular embodiment of the application, the molar ratio of the compound of formula B to the dehydrating agent is 1:10, 1:11, 1:12, 1:13, 1:14 or 1:15. In a more particular embodiment of the application, the molar ratio of the compound of formula B to the dehydrating agent is 1:13.

[0016] In some embodiments of the application, the process for preparing the compound of formula D as described above, the reaction temperature is 5-30°C, preferably 5-20°C, more preferably 5-15°C. In a particular embodiment of the application, the reaction temperature is 10-15°C. In a more particular embodiment of the application, the reaction temperature is 10-12°C.

[0017] In some embodiments of the application, the process for preparing the compound of formula D as described above, the reaction time is 5-30 hours, preferably 5-20 hours, more preferably 10-20 hours. In a particular embodiment of the application, the reaction time is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the application, the reaction time is 16 hours.

[0018] In some embodiments of the application, the process for preparing the compound of formula D as described above, wherein the process for preparing the compound of formula B comprises: iodination of the compound of formula A to obtain the compound of formula B.

[0019]

[0020] In some embodiments of the application, the process for preparing the compound of formula B as described above, the iodination is carried out in the presence of an iodinating agent and a solvent.

[0021] In some embodiments of the application, the process for preparing the compound of formula B as described above, the iodinating agent is selected from the group consisting of iodine element, iodic acid, N-iodosuccinimide or NaICl2, preferably NaICl2or N-iodosuccinimide, more preferably N-iodosuccinimide.

[0022] In some embodiments of the application, the process for preparing a compound of formula B as described above, the solvent is selected from one or more mixed solvents of DMF, DMA, 1,4-dioxane, acetonitrile or tetrahydrofuran, preferably one or more mixed solvents of DMF, 1,4-dioxane or tetrahydrofuran, more preferably DMF or 1,4-dioxane. In a particular embodiment of the application, the solvent is DMF.

[0023] In some embodiments of the application, the process for preparing a compound of formula B as described above, the molar ratio of the compound of formula A to the iodinating agent is 1:1 to 3, preferably 1:1 to 2, more preferably 1:1 to 1.5. In a particular embodiment of the application, the molar ratio of the compound of formula A to the iodinating agent is 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5. In a more particular embodiment of the application, the molar ratio of the compound of formula A to the iodinating agent is 1:1.1.

[0024] In some embodiments of the application, the process for preparing a compound of formula B as described above, the molar volume ratio of the compound of formula A to the solvent is 1 mmol: 0.5 to 3 mL, preferably 1 mmol: 0.5 to 2 mL, more preferably 1 mmol: 0.5 to 1 mL. In a particular embodiment of the application, the molar volume ratio of the compound of formula A to the solvent is 1 mmol: 0.5 mL, 1 mmol: 0.6 mL, 1 mmol: 0.7 mL, 1 mmol: 0.8 mL, 1 mmol: 0.9 mL or 1 mmol: 1 mL. In a more particular embodiment of the application, the molar volume ratio of the compound of formula A to the solvent is 1 mmol: 0.6 mL.

[0025] In some embodiments of the application, the process for preparing a compound of formula B as described above, the reaction temperature of the iodination reaction is 30 to 80 °C, preferably 30 to 60 °C, more preferably 40 to 60 °C. In a particular embodiment of the application, the reaction temperature is 50 to 60 °C. In a more particular embodiment of the application, the reaction temperature is 50 °C.

[0026] In some embodiments of the application, the process for preparing a compound of formula B as described above, the reaction time of the iodination reaction is 5 to 30 hours, preferably 5 to 20 hours, more preferably 10 to 20 hours. In a particular embodiment of the application, the reaction time is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the application, the reaction time is 16 hours.

[0027] In another aspect, the present application provides a method for preparing a compound of formula I, which comprises: (1) subjecting a compound of formula VI to an amino protection reaction to obtain a mixture of a compound of formula V-1 and a compound of formula V-2; (2) reacting a compound of formula D with the mixture of the compound of formula V-1 and the compound of formula V-2 to obtain a mixture of a compound of formula IV-1 and a compound of formula IV-2; (3) subjecting the mixture of the compound of formula IV-1 and the compound of formula IV-2 to a hydrolysis reaction to obtain a mixture of a compound of formula III-1 and a compound of formula III-2; (4) reacting the mixture of the compound of formula III-1 and the compound of formula III-2 with a compound 5 to obtain a mixture of a compound of formula II-1 and a compound of formula II-2; and (5) subjecting the mixture of the compound of formula II-1 and the compound of formula II-2 to a deprotection reaction to obtain the compound of formula I.

[0028]

[0029] In some embodiments of the method for preparing a compound of formula I described above, the compound of formula VI in step (1) is reacted with 2-(trimethylsilyl)ethoxymethyl chloride in the presence of a solvent and a base.

[0030] In some embodiments of the method for preparing a compound of formula I described above, the solvent in step (1) is selected from one or more mixed solvents of methanol, ethanol, diethyl ether, acetone, tetrahydrofuran, dichloromethane, DMF, DMSO, benzene or toluene, preferably one or more mixed solvents of methanol, ethanol, diethyl ether, acetone, tetrahydrofuran or dichloromethane, more preferably one or more mixed solvents of tetrahydrofuran or dichloromethane. In a particular embodiment of the present application, the solvent in step (1) is selected from tetrahydrofuran.

[0031] In some embodiments of the method for preparing a compound of formula I described above, the base in step (1) is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, triethylamine, N,N-diisopropylethylamine, pyridine or piperidine, preferably one or a mixture of potassium carbonate or N,N-diisopropylethylamine. In a particular embodiment of the present application, the base is a mixture of potassium carbonate and N,N-diisopropylethylamine. In a more particular embodiment of the present application, the molar ratio of potassium carbonate to N,N-diisopropylethylamine is 1:1.

[0032] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the compound of formula VI to the base in step (1) is 1:1-6, preferably 1:1-4, more preferably 1:1-2. In a particular embodiment of the application, the molar ratio of the compound of formula VI to the base is 1:2.

[0033] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the compound of formula VI to the base in step (1) is 1:1-6, preferably 1:1-4, more preferably 1:1-2. In a particular embodiment of the application, the molar ratio of the compound of formula VI to the base is 1:2.

[0034] In some embodiments of the above process for preparing a compound of formula I, the molar volume ratio of the compound of formula VI to the solvent in step (1) is 1 mmol: 0.5-5 mL, preferably 1 mmol: 0.8-2 mL, more preferably 1 mmol: 0.9-1.2 mL. In a particular embodiment of the application, the molar volume ratio of the compound of formula VI to the solvent is 1 mmol: 0.9 mL, 1 mmol: 1 mL, 1 mmol: 1.1 mL or 1 mmol: 1.2 mL. In a more particular embodiment of the application, the molar volume ratio of the compound of formula VI to the solvent is 1 mmol: 1 mL.

[0035] In some embodiments of the above process for preparing a compound of formula I, the reaction temperature of the compound of formula VI with 2-(trimethylsilyl)ethoxymethyl chloride in step (1) is -20-10 °C, preferably -10-0 °C, more preferably -5-0 °C. In a particular embodiment of the application, the reaction temperature is 0 °C.

[0036] In some embodiments of the above process for preparing a compound of formula I, the reaction time of the compound of formula VI with 2-(trimethylsilyl)ethoxymethyl chloride in step (1) is 1-10 hours, preferably 2-5 hours. In a particular embodiment of the application, the reaction time is 3 hours.

[0037] In some embodiments of the above process for preparing a compound of formula I, the reaction of the compound of formula D with the mixture of the compound of formula V-1 and the compound of formula V-2 in step (2) is carried out in the presence of a catalyst, a solvent and a base.

[0038] In some embodiments of the application, the process for preparing the compound of formula I, the catalyst in step (2) 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'- bisdiphenylphosphinoferrocene palladium dichloride or tris(dibenzylideneacetone)dipalladium, preferably bis(triphenylphosphine)palladium dichloride or 1,1'- bisdiphenylphosphinoferrocene palladium dichloride, more preferably 1,1'- bisdiphenylphosphinoferrocene palladium dichloride.

[0039] In some embodiments of the application, the process for preparing the compound of formula I, the base in step (2) 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 sodium carbonate, potassium carbonate or cesium carbonate, more preferably potassium carbonate.

[0040] In some embodiments of the application, the process for preparing the compound of formula I, the solvent in step (2) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water, preferably one or more mixed solvents of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile and water, more preferably one or more mixed solvents of tetrahydrofuran, 2-methyltetrahydrofuran and water. In a particular embodiment of the application, the solvent in step (1) is selected from a mixed solvent of tetrahydrofuran and water or a mixed solvent of 2-methyltetrahydrofuran and water. In a more particular embodiment of the application, the solvent in step (2) is selected from a mixed solvent of 2-methyltetrahydrofuran and water.

[0041] In some embodiments of the application, the process for preparing the compound of formula I, the molar ratio of the compound of formula D to the mixture of the compound of formula V-1 and the compound of formula V-2 in step (2) is 1:1-3, preferably 1:1-2, more preferably 1:1-1.5. In a particular embodiment of the application, the molar ratio of the compound of formula D to the mixture of the compound of formula V-1 and the compound of formula V-2 is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5. In a more particular embodiment of the application, the molar ratio of the compound of formula D to the mixture of the compound of formula V-1 and the compound of formula V-2 is 1:1.2.

[0042] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the compound of formula D to the catalyst in step (2) is 1 : 0.01 to 0.1, preferably 1 : 0.01 to 0.05, more preferably 1 : 0.01 to 0.03. In a particular embodiment of the application, the molar ratio of the compound of formula D to the catalyst is 1 : 0.01, 1 : 0.02, or 1 : 0.03. In a more particular embodiment of the application, the molar ratio of the compound of formula D to the catalyst is 1 : 0.02.

[0043] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the compound of formula D to the base in step (2) is 1 : 1 to 5, preferably 1 : 1 to 3, more preferably 1 : 2 to 3. In a particular embodiment of the application, the molar ratio of the compound of formula D to the base is 1 : 2, 1 : 2.1, 1 : 2.2, 1 : 2.3, 1 : 2.4, or 1 : 2.5. In a more particular embodiment of the application, the molar ratio of the compound of formula D to the base is 1 : 2.2.

[0044] In some embodiments of the above process for preparing a compound of formula I, the molar volume ratio of the compound of formula D to the solvent in step (2) is 1 mmol : 2 to 10 mL, preferably 1 mmol : 2 to 5 mL, more preferably 1 mmol : 3 to 5 mL. In a particular embodiment of the application, the molar volume ratio of the compound of formula D to the solvent is 1 mmol : 3 mL, 1 mmol : 4 mL, or 1 mmol : 5 mL. In a more particular embodiment of the application, the molar volume ratio of the compound of formula D to the solvent is 1 mmol : 3 mL.

[0045] In some embodiments of the above process for preparing a compound of formula I, the solvent is a mixture of 2-methyltetrahydrofuran and water, and the volume ratio of the 2-methyltetrahydrofuran to water is 1 to 5 : 1, preferably 2 to 5 : 1, more preferably 2 to 3 : 1. In a particular embodiment of the application, the volume ratio of the 2-methyltetrahydrofuran to water is 2.5 : 1, 2.6 : 1, 2.7 : 1, 2.8 : 1, 2.9 : 1, or 3 : 1. In a more particular embodiment of the application, the volume ratio of the 2-methyltetrahydrofuran to water is 2.6 : 1.

[0046] In some embodiments of the above process for preparing a compound of formula I, the reaction temperature of the compound of formula D with the mixture of the compound of formula V-1 and the compound of formula V-2 in step (2) is 50 to 120 °C, preferably 50 to 100 °C, more preferably 60 to 90 °C. In a particular embodiment of the application, the reaction temperature is 70 to 80 °C. In a more particular embodiment of the application, the reaction temperature is 80 °C.

[0047] In some embodiments of the above process for preparing a compound of formula I, the reaction time of the step (3) is 5 to 30 hours, preferably 5 to 20 hours, more preferably 10 to 20 hours. In a particular embodiment of the present application, the reaction time of the step (3) is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the present application, the reaction time of the step (3) is 16 hours.

[0048] In some embodiments of the above process for preparing a compound of formula I, the step (3) is carried out in the presence of a base and a solvent.

[0049] In some embodiments of the above process for preparing a compound of formula I, the base in the step (3) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide. In a particular embodiment of the present application, the base in the step (3) is selected from 5 mol / L to 10 mol / L aqueous sodium hydroxide solution. In a more particular embodiment of the present application, the base in the step (3) is selected from 5 mol / L aqueous sodium hydroxide solution.

[0050] In some embodiments of the above process for preparing a compound of formula I, the solvent in the step (3) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, water, preferably one or more mixed solvents of methanol, ethanol, isopropanol, water, more preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water. In a particular embodiment of the present application, the solvent in the step (3) is selected from a mixed solvent of ethanol and water.

[0051] In some embodiments of the above process for preparing a compound of formula I, the solvent in the step (3) is a mixed solvent of ethanol and water, and the volume ratio of the ethanol to water is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 to 2. In a particular embodiment of the present application, the volume ratio of the ethanol to water is 1:1, 1:1.5 or 1:2. In a more particular embodiment of the present application, the volume ratio of the ethanol to water is 1:1.5.

[0052] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the base in step (3) is 1 :2 to 20, preferably 1 :5 to 15, more preferably 1 :6 to 12. In a particular embodiment of the application, the molar ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the base is 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, 1 : 11 or 1 : 12. In a more particular embodiment of the application, the molar ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the base is 1 : 10.

[0053] In some embodiments of the above process for preparing a compound of formula I, the molar volume ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the solvent in step (3) is 1 mmol : 1 to 8 mL, preferably 1 mmol : 2 to 6 mL, more preferably 1 mmol : 3 to 4 mL. In a particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the solvent is 1 mmol : 3 mL, 1 mmol : 3.1 mL, 1 mmol : 3.2 mL, 1 mmol : 3.3 mL, 1 mmol : 3.4 mL or 1 mmol : 3.5 mL. In a more particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to the solvent is 1 mmol : 3.4 mL.

[0054] In some embodiments of the above process for preparing a compound of formula I, the reaction temperature of the hydrolysis reaction in step (3) is 50 to 120 °C, preferably 50 to 100 °C, more preferably 60 to 80 °C. In a particular embodiment of the application, the reaction temperature is 70 to 80 °C. In a more particular embodiment of the application, the reaction temperature is 78 °C.

[0055] In some embodiments of the above process for preparing a compound of formula I, the reaction time of the hydrolysis reaction in step (3) is 5 to 30 hours, preferably 5 to 20 hours, more preferably 10 to 20 hours. In a particular embodiment of the application, the reaction time is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the application, the reaction time is 16 hours.

[0056] In some embodiments of the above process for preparing a compound of formula I, the reaction of the mixture of the compound of formula III-1 and the compound of formula III-2 with compound 5 in step (4) is carried out in the presence of a catalyst, a solvent and a base.

[0057] In some embodiments of the present application, the process for preparing a compound of formula I as described above, the catalyst in step (4) 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'- bisdiphenylphosphinoferrocene palladium dichloride or tris(dibenzylideneacetone)dipalladium, preferably tris(dibenzylideneacetone)dipalladium or 1,1'- bisdiphenylphosphinoferrocene palladium dichloride, more preferably tris(dibenzylideneacetone)dipalladium. In a particular embodiment of the present application, the catalyst in step (4) is selected from tris(dibenzylideneacetone)dipalladium, which is further used in the presence of a ligand selected from 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'- binaphthalene or 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene, preferably 4,5- bisdiphenylphosphino-9,9-dimethylxanthene or 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, more preferably 4,5-bisdiphenylphosphino-9,9- dimethylxanthene.

[0058] In some embodiments of the present application, the process for preparing a compound of formula I as described above, 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 sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, more preferably sodium tert-butoxide.

[0059] In some embodiments of the present application, the process for preparing a compound of formula I as described above, the solvent in step (4) is selected from a mixture of one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethyleneglycol dimethyl ether, acetonitrile and water, preferably a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile and water, more preferably a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran and water. In a particular embodiment of the present application, the solvent in step (4) is selected from tetrahydrofuran or 2-methyltetrahydrofuran. In a more particular embodiment of the present application, the solvent in step (4) is selected from tetrahydrofuran.

[0060] In some embodiments of the process for preparing a compound of formula I described above, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the compound 5 in step (4) is 1 : 1 to 3, preferably 1 : 1 to 2, more preferably 1 : 1 to 1.5. In a particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the compound 5 is 1 : 1, 1 : 1.1, 1 : 1.2, 1 : 1.3, 1 : 1.4 or 1 : 1.5. In a more particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the compound 5 is 1 : 1.1.

[0061] In some embodiments of the process for preparing a compound of formula I described above, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the catalyst in step (4) is 1 : 0.01 to 0.1, preferably 1 : 0.01 to 0.05, more preferably 1 : 0.01 to 0.03. In a particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the catalyst is 1 : 0.01, 1 : 0.02 or 1 : 0.03. In a more particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the catalyst is 1 : 0.02.

[0062] In some embodiments of the process for preparing a compound of formula I described above, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the ligand in step (4) is 1 : 0.01 to 0.1, preferably 1 : 0.02 to 0.08, more preferably 1 : 0.02 to 0.05. In a particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the ligand is 1 : 0.02, 1 : 0.03, 1 : 0.04 or 1 : 0.05. In a more particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the ligand is 1 : 0.04.

[0063] In some embodiments of the process for preparing a compound of formula I described above, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the base in step (4) is 1 : 1 to 5, preferably 1 : 1 to 3, more preferably 1 : 1 to 2. In a particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the base is 1 : 1.5, 1 : 1.6, 1 : 1.7, 1 : 1.8, 1 : 1.9 or 1 : 2. In a more particular embodiment of the present application, the molar ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the base is 1 : 1.5.

[0064] In some embodiments of the above process for preparing a compound of formula I, the molar volume ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the solvent in step (4) is 1 mmol: 2-10 mL, preferably 1 mmol: 2-5 mL, more preferably 1 mmol: 3-5 mL. In a particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the solvent is 1 mmol: 3 mL, 1 mmol: 4 mL or 1 mmol: 5 mL. In a more particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula III-1 and the compound of formula III-2 to the solvent is 1 mmol: 3 mL.

[0065] In some embodiments of the above process for preparing a compound of formula I, the reaction temperature of the mixture of the compound of formula III-1 and the compound of formula III-2 with compound 5 is 50-120 °C, preferably 50-100 °C, more preferably 60-80 °C. In a particular embodiment of the application, the reaction temperature is 70-80 °C. In a more particular embodiment of the application, the reaction temperature is 70 °C.

[0066] In some embodiments of the above process for preparing a compound of formula I, the reaction time of the mixture of the compound of formula III-1 and the compound of formula III-2 with compound 5 is 5-30 hours, preferably 5-20 hours, more preferably 10-20 hours. In a particular embodiment of the application, the reaction time is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the application, the reaction time is 17 hours.

[0067] In some embodiments of the above process for preparing a compound of formula I, the deprotection reaction of the mixture of the compound of formula II-1 and the compound of formula II-2 in step (5) is carried out in the presence of a deprotection agent, a solvent and a base.

[0068] In some embodiments of the above process for preparing a compound of formula I, the deprotection agent in step (5) is selected from the group consisting of tetrabutylammonium fluoride, boron trifluoride etherate, trifluoroacetic acid, hydrochloric acid or pyridine p-toluenesulfonate, preferably tetrabutylammonium fluoride or boron trifluoride etherate, more preferably tetrabutylammonium fluoride. In a particular embodiment of the application, the deprotection agent in step (5) is selected from the group consisting of tetrabutylammonium fluoride, which is dissolved in the solvent of step (5).

[0069] In some embodiments of the above process for preparing a compound of formula I, the solvent in step (5) is selected from one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, water, preferably methanol, ethanol, isopropanol or tetrahydrofuran, more preferably tetrahydrofuran. In a particular embodiment of the above process for preparing a compound of formula I, the deprotecting agent in step (5) is selected from a tetrahydrofuran solution of tetrabutylammonium fluoride.

[0070] In some embodiments of the above process for preparing a compound of formula I, the base in step (5) is selected from triethylamine, N,N-diisopropylethylamine, pyridine, N,N- dimethylaminopyridine, ethylenediamine, piperidine, N-methylpiperidine, morpholine or N- methylmorpholine, preferably ethylenediamine or triethylamine, more preferably ethylenediamine.

[0071] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the deprotecting agent in step (5) is 1 :2 to 10, preferably 1 :2 to 8, more preferably 1 :2 to 6. In a particular embodiment of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the deprotecting agent in step (5) is 1 :2, 1 :3, 1 :4, 1 :5 or 1 :6. In a more particular embodiment of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the deprotecting agent in step (5) is 1 :6.

[0072] In some embodiments of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the base in step (5) is 1 :0.1 to 1, preferably 1 :0.2 to 0.8, more preferably 1 :0.5 to 0.8. In a particular embodiment of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the base in step (5) is 1 :0.5, 1 :0.6, 1 :0.7, or 1 :0.8. In a more particular embodiment of the above process for preparing a compound of formula I, the molar ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the base in step (5) is 1 :0.5.

[0073] In some embodiments of the application, the process for preparing a compound of formula I, the molar volume ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the solvent in step (5) is 1 mmol: 1-8 mL, preferably 1 mmol: 2-6 mL, more preferably 1 mmol: 3-6 mL. In a particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the solvent is 1 mmol: 3 mL, 1 mmol: 4 mL, 1 mmol: 5 mL or 1 mmol: 6 mL. In a particular embodiment of the application, the molar volume ratio of the mixture of the compound of formula II-1 and the compound of formula II-2 to the solvent is 1 mmol: 6 mL.

[0074] In some embodiments of the application, the process for preparing a compound of formula I, the reaction temperature of the deprotection reaction in step (5) is 50-120 °C, preferably 50-100 °C, more preferably 60-80 °C. In a particular embodiment of the application, the reaction temperature is 60-70 °C. In a more particular embodiment of the application, the reaction temperature is 65-70 °C.

[0075] In some embodiments of the application, the process for preparing a compound of formula I, the reaction time of the deprotection reaction in step (5) is 5-30 hours, preferably 5-20 hours, more preferably 10-20 hours. In a particular embodiment of the application, the reaction time is 15, 16, 17, 18, 19 or 20 hours. In a more particular embodiment of the application, the reaction time is 17 hours.

[0076] In some embodiments of the application, the process for preparing a compound of formula I, the mixture of the compound of formula V-1 and the compound of formula V-2 in steps (2)-(5) can be the compound of formula V-1 or the compound of formula V-2, the mixture of the compound of formula IV-1 and the compound of formula IV-2 can be the compound of formula IV-1 or the compound of formula IV-2, the mixture of the compound of formula III-1 and the compound of formula III-2 can be the compound of formula III-1 or the compound of formula III-2, and the mixture of the compound of formula II-1 and the compound of formula II-2 can be the compound of formula II-1 or the compound of formula II-2.

[0077] In another aspect, the application also provides a process for preparing a compound of formula I, which comprises: reacting a compound of formula D with a compound of formula V-1 to obtain a compound of formula IV-1; subjecting the compound of formula IV-1 to a hydrolysis reaction to obtain a compound of formula III-1; reacting the compound of formula III-1 with a compound 5 to obtain a compound of formula II-1; and subjecting the compound of formula II-1 to a deprotection reaction to obtain a compound of formula I.

[0078] In another aspect, the application also provides a process for preparing a compound of formula I, which comprises: reacting a compound of formula D with a compound of formula V-1 to obtain a compound of formula IV-1; subjecting the compound of formula IV-1 to a hydrolysis reaction to obtain a compound of formula III-1; reacting the compound of formula III-1 with a compound 5 to obtain a compound of formula II-1; and subjecting the compound of formula II-1 to a deprotection reaction to obtain a compound of formula I.

[0079] In some embodiments of the present application, the above-mentioned method for preparing the compound of formula I, the steps are as described in the above steps (2), (3), (4) and (5).

[0080] In some embodiments of the present application, the above-mentioned method for preparing the compound of formula I, the steps are as described in the above steps (2), (3), (4) and (5).

[0081]

[0082] In some embodiments of the present application, the above-mentioned method for preparing the compound of formula I, the steps are as described in the above steps (2), (3), (4) and (5).

[0083] In some embodiments of the present application, the above-mentioned method for preparing the compound of formula I, the method for preparing the compound 5 comprises: reacting the compound 4 and 3-oxetanone to obtain the compound 5.

[0084]

[0085] In some embodiments of the present application, the above-mentioned method for preparing the compound 5 is carried out in the presence of a reducing agent, a catalyst and a solvent.

[0086] In some embodiments of the present application, the above-mentioned reducing agent in the method for preparing the compound 5 is selected from sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride or sodium cyanoborohydride, preferably sodium triacetoxyborohydride or sodium cyanoborohydride, more preferably sodium cyanoborohydride.

[0087] In some embodiments of the present application, the above-mentioned catalyst in the method for preparing the compound 5 is selected from zinc chloride, aluminum trichloride, hydrochloric acid, acetic acid or trifluoroacetic acid, preferably zinc chloride, acetic acid or hydrochloric acid, more preferably zinc chloride.

[0088] In some embodiments of the present application, the above-mentioned solvent in the method for preparing the compound 5 is selected from one or more mixed solvents of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane and water, preferably methanol, ethanol or tetrahydrofuran, more preferably ethanol.

[0089] In some embodiments of the present application, the above-mentioned method for preparing the compound 5, the molar ratio of the compound 4 to 3-oxetanone is 1:1-5, preferably 1:2-5, more preferably 1:2-3.

[0090] In some embodiments of the present application, the molar ratio of compound 4 to reducing agent in the above preparation method of compound 5 is 1:1-5, preferably 1:2-5, more preferably 1:2-3.

[0091] In some embodiments of the present application, the molar ratio of compound 4 to catalyst in the above preparation method of compound 5 is 1:1-5, preferably 1:2-5, more preferably 1:2-3.

[0092] In some embodiments of the present application, the molar volume ratio of compound 4 to solvent in the above preparation method of compound 5 is 1 mmol: 1-8 mL, preferably 1 mmol: 2-6 mL, more preferably 1 mmol: 3-6 mL.

[0093] In some embodiments of the present application, the above compound 5 can also be prepared according to WO2021047584.

[0094] In some embodiments of the present application, the above compound 5 can be purchased by a commercially available route.

[0095] In another aspect, the present application provides a preparation method of a compound of formula I, characterized in that it comprises: (i) iodination of a compound of formula A to obtain a compound of formula B; (ii) reaction of the compound of formula B with a compound of formula C to obtain a compound of formula D; (iii) reaction of the compound of formula D with a mixture of a compound of formula V-1 and a compound of formula V-2 to obtain a mixture of a compound of formula IV-1 and a compound of formula IV-2; (iv) hydrolysis of the mixture of the compound of formula IV-1 and the compound of formula IV-2 to obtain a mixture of a compound of formula III-1 and a compound of formula III-2; (v) reaction of the mixture of the compound of formula III-1 and the compound of formula III-2 with compound 5 to obtain a mixture of a compound of formula II-1 and a compound of formula II-2; (vi) deprotection of the mixture of the compound of formula II-1 and the compound of formula II-2 to obtain a compound of formula I.

[0096]

[0097] wherein the reaction conditions of steps (i), (ii), (iii), (iv), (v) and (vi) are as described above in the preparation of the compound of formula D, the preparation of the compound of formula B, steps (2), (3), (4) and (5) of the preparation of the compound of formula I, respectively.

[0098] In another aspect, the present application also provides a preparation method of a compound of formula I, characterized in that the above step (iii) is directly reacted using a compound of formula V-1 or a compound of formula V-2, and the reaction conditions of each step are unchanged, to obtain the corresponding subsequent product, respectively.

[0099] In another aspect, the present application provides the use of a compound as follows in the preparation of a compound of formula I,

[0100]

[0101] In another aspect, the present application provides the use of a compound as follows in the preparation of a compound of formula I,

[0102]

[0103] In another aspect, the present application provides the use of a method for preparing a compound of formula D in the preparation of a compound of formula I, characterized in that the method comprises: reacting a compound of formula B with a compound of formula C to obtain a compound of formula D,

[0104]

[0105] wherein the reaction of the compound of formula B with the compound of formula C is carried out in the presence of a base and a dehydrating agent, and the reaction conditions are as described above.

[0106] The preparation of the compound of formula I of the present application also comprises the purification of the compound of formula I.

[0107] In some embodiments of the present application, the purification of the compound of formula I comprises: stirring the crude compound of formula I in a solvent, filtering, and drying to obtain the pure compound of formula I.

[0108] In some embodiments of the present application, in the purification of the compound of formula I, the solvent is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, and water, preferably one or more mixed solvents of methanol, ethanol, acetone, and water, more preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water. In a specific embodiment of the present application, the solvent is selected from a mixed solvent of ethanol and water. In a more specific embodiment of the present application, the solvent is selected from a mixed solvent of anhydrous ethanol and water.

[0109] In some embodiments of the present application, in the purification of the compound of formula I, the solvent is selected from a mixed solvent of ethanol and water, and the volume ratio of the ethanol and water is 1:1-3, preferably 1:1-2, more preferably 1:1.5-2. In a specific embodiment of the present application, the volume ratio of the ethanol and water is 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2. In a more specific embodiment of the present application, the volume ratio of the ethanol and water is 1:2.

[0110] In some embodiments of the present application, the stirring temperature in the purification of the compound of formula I is 5-30°C, preferably 10-30°C, more preferably 20-30°C. In a particular embodiment of the present application, the stirring temperature is 20°C.

[0111] In some embodiments of the present application, the stirring time in the purification of the compound of formula I is 5-30 hours, preferably 5-20 hours, more preferably 10-20 hours. In a particular embodiment of the present application, the stirring time is 16 hours.

[0112] In some embodiments of the present application, the compound of formula I can be further prepared into hydrochloride.

[0113] In some embodiments of the present application, the preparation of the hydrochloride of the compound of formula I comprises: dissolving the compound of formula I in a solvent, then adding hydrochloric acid and stirring, filtering, adding a second solvent to the filtrate, filtering, and drying to obtain the hydrochloride of the compound of formula I.

[0114] In some embodiments of the present application, the hydrochloride of the compound of formula I is a monohydrochloride of the compound of formula I.

[0115] In some embodiments of the present application, the preparation of the hydrochloride of the compound of formula I, the solvent is selected from one or more mixed solvents of formic acid, acetic acid, propionic acid, acetic acid, methanol, ethanol, isopropanol, ethylene glycol, n-butanol, acetone, tetrahydrofuran, acetonitrile, water, preferably one or more mixed solvents of formic acid, acetic acid, water, more preferably a mixed solvent of formic acid and water.

[0116] In some embodiments of the present application, the preparation of the hydrochloride of the compound of formula I, the hydrochloric acid can be hydrogen chloride gas, concentrated hydrochloric acid or aqueous hydrochloric acid, preferably aqueous hydrochloric acid, more preferably 1-2 mol / L aqueous hydrochloric acid. In a particular embodiment of the present application, the hydrochloric acid is selected from 1 mol / L aqueous hydrochloric acid.

[0117] In some embodiments of the present application, the preparation of the hydrochloride of the compound of formula I, the second solvent is selected from one or more mixed solvents of methanol, ethanol, isopropanol, ethylene glycol, n-butanol, acetone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, dichloromethane, ethyl acetate, 1,2-dichloromethane, n-hexane, diethyl ether, preferably ethanol, isopropanol, ethylene glycol or methyl tert-butyl ether, more preferably ethanol.

[0118] In the present application, all tautomeric forms are included within the scope of the present application, for example and are tautomeric forms.

[0119] The compound of formula A, the compound of formula C, the compound of formula V, compound 4, and 3-oxetanone in the present application can be purchased by commercially available route.

[0120] The preparation method of the compound of formula I and the intermediate compound of formula D provided in the present application has the following advantages:

[0121] (i) The intermediate post-treatment in the preparation of the compound of formula I in the present application does not use silica gel column chromatography, the post-treatment operation is simple, and is economical and easy to obtain.

[0122] (ii) The starting material and reagent in the preparation of the compound of formula I in the present application are cheap and easy to obtain, the total reaction steps are also shortened, the total yield is improved, the purity of the key intermediate and the final product is relatively high, and it is very suitable for industrial production.

[0123] In the present application, K2CO3 represents potassium carbonate; NIS represents N-iodosuccinimide; NBS represents N-bromosuccinimide; DMSO represents dimethyl sulfoxide; DIEA represents N,N-diisopropylethylamine; THF represents tetrahydrofuran; DMF represents N,N-dimethylformamide; DMA represents dimethylacetamide; TBAF represents tetrabutylammonium fluoride; SEM-Cl represents 2-(trimethylsilyl)ethoxymethyl chloride; t-BuONa represents sodium tert-butoxide; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; X-Phos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd(OAc)2 represents palladium acetate; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; TLC represents thin layer chromatography; and HPLC represents high performance liquid chromatography. DETAILED DESCRIPTION

[0124] The following specific examples are intended to enable those skilled in the art to more clearly understand and implement the present application. They should not be considered as limiting the scope of the protection of the present application, but only as illustrative and typical of the present application. Those skilled in the art should understand that there are other synthetic routes to form the compounds in the present application, and the following provided are non-limiting examples.

[0125] Unless otherwise specified, the temperature is in Celsius. The solvents used in the present application can be commercially available.

[0126] Example 1 Preparation of the compound of formula D

[0127]

[0128] Step 1: Preparation of the compound of formula B

[0129]

[0130] Into a 1 L three-necked flask, DMF (400 mL) was added, followed by the compound of formula A (94 g, 0.61 mol), and NIS (152 g, 0.67 mol) was added portionwise with stirring. The temperature was raised to 50 °C, and the reaction was allowed to proceed for 16 h. HPLC indicated that the starting material had been completely converted. The temperature was lowered to 30 °C, and water (2 L) was added, and stirring was continued for 15 min. Filtration, washing of the filter cake with water, and drying gave the compound of formula B (161 g) in a yield of 94.6%.

[0131] 1 H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.62-8.61 (d, 1H), 7.74-7.71 (m, 1H), 6.49-6.47 (d, 1H), 2.89-2.88 (d, 3H).

[0132] Step 2: Preparation of the compound of formula D

[0133]

[0134] Into a 2 L three-necked flask, acetic anhydride (725 mL, 7.72 mol) was added, followed by the compound of formula B (161 g, 0.58 mol), and the compound of formula C (310 g, 1.73 mol). DIEA (149 g, 1.15 mol) was added dropwise slowly with stirring, and the temperature was controlled at 10 °C. After the dropwise addition was completed, the reaction was allowed to proceed for 16 h at room temperature. HPLC indicated that the starting material had been completely converted. Water (1.5 L) was added slowly to the reaction with stirring. The mixture was stirred for 0.5 h at 0-5 °C. Filtration, washing of the filter cake with water, and drying gave the compound of formula D (241 g) in a yield of 98.4% and a purity of 97.4%.

[0135] 1 H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.83 (s, 1H), 7.97-7.95 (m, 2H), 7.93-7.90 (m, 1H), 7.68-7.65 (m, 1H), 7.61-7.58 (m, 2H), 7.31-7.29 (m, 1H), 3.76 (s, 3H).

[0136] Preparation of the compound of Example 2, 5

[0137]

[0138] Into a 3L flask, add ethanol (1L), compound 4 (77g, 0.32mol) sequentially, cool to 10-15℃, stir for 10min, then add 3-oxetanone (46g, 0.64mol), zinc chloride (87g, 0.64mol) in batches, add sodium cyanoborohydride (40g, 0.64mol) in batches, warm to 45℃, react for 12h. HPLC detection shows that the starting material has been completely converted, cool to 10℃, add saturated sodium carbonate aqueous solution (400mL) to quench the reaction, then add sodium carbonate solid (87g, 0.82mol), adjust the pH to 8, add 2-methyltetrahydrofuran (400mL), stir for 1h. Filter, wash the filter cake with 2-methyltetrahydrofuran (400mL), combine the filtrate and concentrate under reduced pressure to remove the organic solvent. Add 5% sodium hydroxide aqueous solution (200mL) to the concentrated solution and beat for 1h, filter, wash the filter cake with water (200mL) for 0.5h, filter, wash the filter cake with water (100mL), and dry to obtain compound 5 (79g) with a yield of 82.9% and a purity of 99.0%.

[0139] Example 3 Preparation of the hydrochloride salt of the compound of formula I

[0140]

[0141] Step 1: Preparation of a mixture of a compound of formula V-1 and a compound of formula V-2

[0142] Into a 2L flask, add 2-methyltetrahydrofuran (500mL), compound of formula VI (100g, 0.52mol), potassium carbonate (72g, 0.52mol), and DIEA (67g, 0.52mol) sequentially, stir for 10min, and cool to below 0℃. Add SEM-Cl (112g, 0.67mol) dropwise while controlling the temperature below 0℃. Continue to react for 3h after dropping is completed. HPLC detection shows that the starting material has been completely converted, and warm to room temperature for the next step.

[0143] Step 2: Preparation of a mixture of a compound of formula IV-1 and a compound of formula IV-2

[0144] To the reactant of the previous step, 2-methyltetrahydrofuran (910 mL), water (360 mL), potassium carbonate (130 g, 0.94 mol), D compound (180 g, 0.43 mol), Pd(dppf)Cl2(7 g, 9.57 mmol) were added successively, and after being protected by nitrogen, the mixture was stirred and warmed to 80°C, and reacted for 16 hours. HPLC detection showed that the starting material had been completely converted. The mixture was cooled to room temperature, stirred for 1 hour, and then n-heptane (880 mL), water (530 mL) were added. The mixture was cooled to below 0°C, stirred for 0.5 hours, filtered, and the filter cake was washed with n-heptane (200 mL). After drying, a mixture of compound of formula IV-1 and compound of formula IV-2 (185 g) was obtained, with a yield of 88.2% and a purity of 97.1%.

[0145] 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.98-8.93 (m, 1H), 8.14-8.00 (m, 3H), 7.77-7.54 (m, 5H), 6.84-6.63 (m, 1H), 5.53-5.44 (m, 2H), 3.86-3.83 (m, 3H), 3.67-3.52 (m, 2H), 0.92-0.79 (m, 2H), 0.03-0.00 (m, 9H).

[0146] Step 3: Preparation of a mixture of compound of formula III-1 and compound of formula III-2

[0147] To a 3L three-necked flask were added ethanol (500 mL), a mixture of compound of formula IV-1 and compound of formula IV-2 (180 g, 0.36 mol), and aqueous sodium hydroxide solution (5M, 750 mL, 3.75 mol) successively. The mixture was stirred and warmed to 75-80°C, and reacted for 16 hours. HPLC detection showed that the starting material had been completely converted. The mixture was cooled to room temperature, and water (600 mL) was added to the reaction solution. The mixture was cooled to below 10°C, and stirred for 0.5 hours. The mixture was filtered, and the filter cake was washed with water (300 mL). After drying, a mixture of compound of formula III-1 and compound of formula III-2 (140 g) was obtained, with a yield of 98.7% and a purity of 98.7%.

[0148] 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.98-8.93 (m, 1H), 8.14-8.00 (m, 3H), 7.77-7.54 (m, 5H), 6.84-6.63 (m, 1H), 5.53-5.44 (m, 2H), 3.86-3.83 (m, 3H), 3.67-3.52 (m, 2H), 0.92-0.79 (m, 2H), 0.03-0.00 (m, 9H).

[0149] Step 4: Preparation of the mixture of compound of formula II-1 and compound of formula II-2

[0150] Into a 3L flask, was added THF (1000 mL), the mixture of compound of formula III-1 and compound of formula III-2 (124 g, 0.32 mol), compound 5 (100 g, 0.34 mol), Pd2(dba)3 (6 g, 6.5 mmol), Xantphos (7.4 g, 12.8 mmol), t-BuONa (46 g, 0.48 mol) successively, stirred, protected by nitrogen, warmed to 65-70 °C, reacted for 17 hours, HPLC detection showed that the starting material had been completely converted. Cooled to below 0 °C, added water (200 mL), n-heptane (1000 mL) and stirred for 1 hour. Filtered, oven-dried to obtain the crude product of the mixture of compound of formula II-1 and compound of formula II-2 (202 g).

[0151] Into a 3L flask, was added THF (2020 mL), the crude product of the mixture of compound of formula II-1 and compound of formula II-2 (202 g) successively, stirred, warmed to 65-70 °C, continued to stir for 1 hour after the solution was clear, added mercapto silica gel (40 g), continued to stir for 2 hours. Filtered while hot, the filter cake was rinsed with hot THF, the filtrate was combined, concentrated to a small volume, added n-heptane (1000 mL), cooled to below 5 °C, stirred for 1 hour, filtered, the filter cake was oven-dried to obtain the crude product of the mixture of compound of formula II-1 and compound of formula II-2 (172 g).

[0152] Into a 3L flask, was added THF (1720 mL), the crude product obtained above (172 g) successively, stirred, warmed to 65-70 °C, continued to stir for 1 hour after the solution was clear, added mercapto silica gel (36 g), continued to stir for 2 hours. Filtered while hot, the filter cake was rinsed with hot THF, the filtrate was combined, concentrated to a small volume, added n-heptane (800 mL), cooled to below 5 °C, stirred for 1 hour, filtered, the filter cake was oven-dried to obtain the mixture of compound of formula II-1 and compound of formula II-2 (150 g), yield: 77.4%, purity: 99.1%.

[0153] 1 H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.93 (s, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.65-7.42 (m, 4H), 6.67 (s, 1H), 5.50 (s, 2H), 4.68-4.56 (m, 4H), 3.90 (s, 3H), 3.62-3.54 (m, 3H), 3.23 (s, 4H), 2.51 (s, 4H), 0.88-0.85 (m, 2H), 0.10-0.00 (m, 9H).

[0154] Step 5: Preparation of the compound of formula I

[0155] Into a 2L three-necked flask, was added TBAF in THF (1.0M, 1000mL), a mixture of the compound of formula II-1 and the compound of formula II-2 (100g, 0.165mol), and ethylenediamine (5g, 0.083mol) in sequence, and stirred to warm to 65-70°C. The reaction was carried out for 17 hours, and HPLC detection showed that the starting material had been completely converted. THF (900mL) was added to the reaction solution, and gradient cooling to room temperature was continued for 16 hours. Filtration, THF rinsing of the filter cake, and oven drying gave the crude compound of formula I (90g).

[0156] Into a 1L single-necked flask, was added water (1000mL), ethanol (500mL), and the crude compound of formula I (90g) in sequence, and stirred at room temperature for 16 hours. Filtration and oven drying gave the compound of formula I (64g), with a yield of 81.1% and a purity of 98.9%.

[0157] Step 6: Preparation of the hydrochloride salt of the compound of formula I

[0158]

[0159] Into a 2L three-necked flask, was added water (200mL), and stirred to warm to 35-38°C. The compound of formula I (50g, 0.10mol) was added in portions, and stirred for 0.5 hours. 98% formic acid (100mL) was added dropwise to the reaction flask, and the dropwise addition was completed in about 1 hour. Stirring was continued for 1 hour, and aqueous hydrochloric acid (1N, 160mL) was added dropwise. The dropwise addition was completed in about 2 hours, and stirring was continued for 2 hours. Ethanol (900mL) was added dropwise, and the dropwise addition was completed in about 5 hours. Stirring was continued for 2 hours, and filtration was carried out. Oven drying of the filter cake gave the hydrochloride salt of the compound of formula I (47g), with a yield of 87.4%.

[0160] 1 H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 11.72 (s, 1H), 9.07 (s, 1H), 8.87 (s, 1H), 8.10 (s, 1H), 7.95-7.85 (m, 2H), 7.50 (s, 1H), 7.43-7.37 (m, 2H), 6.74-6.72 (m, 1H), 4.90-4.51 (m, 5H), 3.82-3.79 (m, 4H), 3.62-3.54 (m, 3H), 3.15-3.06 (m, 4H).

Claims

1. A process for the preparation of a compound of formula D, characterized by, comprising: the compound of formula B is reacted with a compound of formula C to obtain a compound of formula D, 2. A process for the preparation of a compound of formula D according to claim 1, wherein the reaction of the compound of formula B with the compound of formula C is carried out in the presence of a base and a dehydrating agent; wherein, the base is selected from an organic base or an inorganic base; the inorganic base is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the organic base is selected from triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine; wherein the dehydrating agent is selected from acetic anhydride, propionic anhydride, phthalic anhydride or butenedioic anhydride.

3. The process for the preparation of a compound of formula D according to claim 2, wherein, The molar ratio of the compound of formula B to the compound of formula C is 1:1-7, the molar ratio of the compound of formula B to the base is 1:1-5, and the molar ratio of the compound of formula B to the dehydrating agent is 1:1-20.

4. A process for the preparation of a compound of formula D as claimed in any one of claims 1 to 3, wherein, The preparation method of the compound of formula B comprises: iodination of the compound of formula A to obtain the compound of formula B, 5. The process of claim 4 for the preparation of a compound of formula D, wherein, In the preparation method of the compound of formula B, the iodination is carried out in the presence of an iodinating agent and a solvent, wherein the iodinating agent is selected from iodine, iodic acid, N-iodosuccinimide or NaICl2, and the solvent is selected from one or more mixed solvents of DMF, DMA, 1,4-dioxane, acetonitrile or tetrahydrofuran.

6. A process for the preparation of a compound of formula I, characterized in that, comprising: (1) the compound of formula VI is subjected to an amino protection reaction to obtain a mixture of the compound of formula V-1 and the compound of formula V-2; (2) the compound of formula D is reacted with the mixture of the compound of formula V-1 and the compound of formula V-2 to obtain a mixture of the compound of formula IV-1 and the compound of formula IV-2; (3) the mixture of the compound of formula IV-1 and the compound of formula IV-2 is subjected to a hydrolysis reaction to obtain a mixture of the compound of formula III-1 and the compound of formula III-2; (4) the mixture of the compound of formula III-1 and the compound of formula III-2 is reacted with compound 5 to obtain a mixture of the compound of formula II-1 and the compound of formula II-2; (5) the mixture of the compound of formula II-1 and the compound of formula II-2 is subjected to a deprotection reaction to obtain the compound of formula I, Alternatively, steps (2) to (5) comprise: the compound of formula D is reacted with the compound of formula V-1 to obtain the compound of formula IV-1; the compound of formula IV-1 is subjected to a hydrolysis reaction to obtain the compound of formula III-1; the compound of formula III-1 is reacted with compound 5 to obtain the compound of formula II-1; and the compound of formula II-1 is subjected to a deprotection reaction to obtain the compound of formula I, Alternatively, steps (2) to (5) comprise: the compound of formula D is reacted with the compound of formula V-2 to obtain the compound of formula IV-2; the compound of formula IV-2 is subjected to a hydrolysis reaction to obtain the compound of formula III-2; the compound of formula III-2 is reacted with compound 5 to obtain the compound of formula II-2; and the compound of formula II-2 is subjected to a deprotection reaction to obtain the compound of formula I, 7. A process for the preparation of a compound of formula I, characterized in that, comprising: (i) the compound of formula A is subjected to an iodination reaction to obtain the compound of formula B; (ii) the compound of formula B is reacted with the compound of formula C to obtain the compound of formula D; (iii) reacting the compound of formula D with a mixture of a compound of formula V-1 and a compound of formula V-2 to give a mixture of a compound of formula IV-1 and a compound of formula IV-2; (iv) hydrolyzing the mixture of a compound of formula IV-1 and a compound of formula IV-2 to give a mixture of a compound of formula III-1 and a compound of formula III-2; (v) reacting the mixture of a compound of formula III-1 and a compound of formula III-2 with compound 5 to give a mixture of a compound of formula II-1 and a compound of formula II-2; (vi) deprotecting the mixture of a compound of formula II-1 and a compound of formula II-2 to give a compound of formula I, 8. A compound of formula 9. A compound of formula 10. A process for the preparation of a compound of formula I, characterized in that, comprising: a process for preparing a compound of formula D according to claim 1, 11. Use of a compound according to claim 8 or 9 for the preparation of a compound of formula I,

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