A process for the preparation of an isothiazolo[5,4-d]pyrimidine irak4 inhibitor

Abstract

Provided is a preparation method of an isothiazolo[5,4-d]pyrimidine IRAK4 inhibitor, in particular to a preparation method of a compound of formula (I) and an intermediate compound 6. The method for obtaining the trans isomer has the advantages of mild reaction conditions, short reaction steps, short reaction time, simple post-treatment operation, high isomer purity and the like, and is very suitable for industrial production.

Description

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202111508482.8 filed on December 10, 2021 with the State Intellectual Property Office of the People’s Republic of China, the contents of which are incorporated herein in their entirety by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of pharmaceutical chemical industry, and relates to a preparation method of an isothiazolo[5,4-d]pyrimidine IRAK4 inhibitor, in particular to a preparation method of methyl 4-((1R,4R)-4-((3-methyl-6-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)isothiazolo[5,4-d]pyrimidin-4-yl)amino)cyclohexyl)piperazine-1-carboxylate and an intermediate compound 6, methyl 4-((1R,4R)-4-aminocyclohexyl)piperazine-1-carboxylate. BACKGROUND

[0004] Interleukin 1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase belonging to the tyrosine-like kinase (TLK) family, which is a key node in the innate immune response involving interleukin-1, interleukin-18, interleukin-33 receptors and Toll-like receptors. After the extracellular signaling molecules bind to the interleukin receptor or Toll-like receptor, a MyD88:IRAK4:IRAK1 / 2 multi-protein complex is recruited, leading to the phosphorylation of IRAK1 / 2, mediating a series of downstream signaling, thereby activating the p38, JNK and NF-kB signaling pathways, and ultimately leading to the expression of pro-inflammatory cytokines. Clinical pathological studies have shown that individuals with IRAK4 mutations have a protective effect on chronic lung disease and inflammatory bowel disease. IRAK4 deficiency is not lethal in itself, and individuals can survive to adulthood with reduced risk of infection as they age. Therefore, IRAK4 has become an important therapeutic target, attracting extensive research interest.

[0005] WO2021147968 discloses a compound of formula (I) and a preparation method of the compound of formula (I), which is shown in the following route:

[0006]

[0007] Among them, intermediate compound 6 is a key intermediate for the preparation of the compound of formula (I), but the preparation method of intermediate compound 6 introduces an expensive trans-isomer compound 2 as a starting material, and a metal palladium catalyst is introduced for debenzyl protection, and the preparation route of the method is relatively long, and the yield is low, which is not suitable for industrial production.

[0008] Therefore, it is necessary to provide a preparation method of the compound of formula (I) which is more economical, convenient, higher in yield and more suitable for industrial production. SUMMARY

[0009] In one aspect, the present application provides a preparation method of intermediate compound 6, which comprises: (a) reacting a compound of formula II in the presence of hydrochloric acid and a solvent to obtain intermediate compound 6.

[0010]

[0011] In some embodiments of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from hydrogen chloride gas, or a solution of hydrogen chloride, such as an aqueous solution of hydrogen chloride, an organic solvent solution of hydrogen chloride, or a mixed solution of both. For example, the hydrochloric acid in step (a) is a solution of hydrogen chloride, including an aqueous solution and an organic solvent solution or a mixed solution thereof. In some embodiments of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from a hydrochloric acid / water solution, a hydrochloric acid / methanol solution, a hydrochloric acid / ethyl acetate solution, a hydrochloric acid / acetone solution, a hydrochloric acid / ethanol solution, or a hydrochloric acid / dioxane solution. In some embodiments of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from a hydrochloric acid / water solution, a mixed solution of hydrogen chloride / methanol and water, a mixed solution of hydrogen chloride / ethyl acetate and water, a mixed solution of hydrogen chloride / acetone and water, a mixed solution of hydrogen chloride / ethanol and water, a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / methanol solution, a hydrogen chloride / ethanol solution, or a hydrogen chloride / dioxane solution. In some embodiments of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from concentrated hydrochloric acid, a concentrated hydrochloric acid / methanol solution, a concentrated hydrochloric acid / ethyl acetate solution, a concentrated hydrochloric acid / acetone solution, a concentrated hydrochloric acid / ethanol solution, a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / methanol solution, a hydrogen chloride / ethanol solution, or a hydrogen chloride / dioxane solution. In some embodiments of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from concentrated hydrochloric acid, a hydrochloric acid / methanol solution, a hydrochloric acid / ethyl acetate solution, a hydrochloric acid / acetone solution, a hydrochloric acid / ethanol solution, a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / methanol solution, a hydrogen chloride / ethanol solution, or a hydrogen chloride / dioxane solution. Preferably, the hydrochloric acid in step (a) is selected from 30%-60% concentrated hydrochloric acid; or, the hydrochloric acid in step (a) is selected from a 1-10 mol / L hydrogen chloride solution, including an organic solvent solution of hydrogen chloride, or a mixed solution of hydrogen chloride in an organic solvent and water. More preferably, the hydrochloric acid in step (a) is selected from 30%-60% concentrated hydrochloric acid, or is selected from a 1-10 mol / L hydrochloric acid / methanol solution, a hydrochloric acid / ethyl acetate solution, a hydrochloric acid / acetone solution, a hydrochloric acid / ethanol solution, a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / methanol solution, a hydrogen chloride / ethanol solution, or a hydrogen chloride / dioxane solution. Further preferably, the hydrochloric acid in step (a) is selected from 30%-40% concentrated hydrochloric acid. Further preferably, the hydrochloric acid in step (a) is selected from 36%-38% concentrated hydrochloric acid. In a particular embodiment of the present application, the hydrochloric acid in step (a) of the process for preparing the intermediate compound 6 is selected from 37% concentrated hydrochloric acid.

[0012] In some embodiments of the application, the solvent in step (a) of the process for the preparation of intermediate compound 6 is selected from one of ethanol, acetone, methyl-tert-butyl ether. In a particular embodiment of the application, the solvent in step (a) of the process for the preparation of intermediate compound 6 is selected from acetone.

[0013] In some embodiments of the application, the molar ratio of the compound of formula II to hydrochloric acid in step (a) of the process for the preparation of intermediate compound 6 is 1 : (1-10); preferably, the molar ratio of the compound of formula II to hydrochloric acid in step (a) is 1 : (1-5); further preferably, the molar ratio of the compound of formula II to hydrochloric acid in step (a) is 1 : (3-5). Still further preferably, the molar ratio of the compound of formula II to hydrochloric acid in step (a) is 1 :3, 1 :3.5, 1 :4, 1 :4.5, 1 :5. In a particular embodiment of the application, the molar ratio of the compound of formula II to hydrochloric acid in step (a) of the process for the preparation of intermediate compound 6 is 1 :5.

[0014] In some embodiments of the application, the molar ratio of the compound of formula II to hydrogen chloride in step (a) of the process for the preparation of intermediate compound 6 is 1 : (1-10); preferably, the molar ratio of the compound of formula II to hydrogen chloride in step (a) is 1 : (1-5); further preferably, the molar ratio of the compound of formula II to hydrogen chloride in step (a) is 1 : (3-5). Still further preferably, the molar ratio of the compound of formula II to hydrogen chloride in step (a) is 1 :3, 1 :3.5, 1 :4, 1 :4.5, 1 :5. In a particular embodiment of the application, the molar ratio of the compound of formula II to hydrogen chloride in step (a) of the process for the preparation of intermediate compound 6 is 1 :5.

[0015] In some embodiments of the present application, the molar volume ratio of the compound of formula II to the solvent in step (a) of the method for preparing the intermediate compound 6 is 1 mmol: (1-5 mL); preferably, the molar volume ratio of the compound of formula II to the solvent in step (a) is 1 mmol: (1-3 mL); further preferably, the molar volume ratio of the compound of formula II to the solvent in step (a) is 1 mmol: (1-2 mL). Still further preferably, the molar volume ratio of the compound of formula II to the solvent in step (a) is 1 mmol: 1 mL, 1 mmol: 1.1 mL, 1 mmol: 1.2 mL, 1 mmol: 1.3 mL, 1 mmol: 1.4 mL, 1 mmol: 1.5 mL, 1 mmol: 1.6 mL, 1 mmol: 1.7 mL, 1 mmol: 1.8 mL, 1 mmol: 1.9 mL, or 1 mmol: 2 mL. In a particular embodiment of the present application, the molar volume ratio of the compound of formula II to the solvent in step (a) of the method for preparing the intermediate compound 6 is 1 mmol: 1.7 mL.

[0016] In some embodiments of the present application, the reaction temperature of step (a) of the method for preparing the intermediate compound 6 is 10-50 °C; preferably, the reaction temperature of step (a) is 10-30 °C; further preferably, the reaction temperature of step (a) is 20-30 °C. In a particular embodiment of the present application, the reaction temperature of step (a) of the method for preparing the intermediate compound 6 is 25-30 °C.

[0017] In some embodiments of the present application, the reaction time of step (a) of the method for preparing the intermediate compound 6 is 1-10 hours; preferably, the reaction time of step (a) is 2-6 hours; further preferably, the reaction time of step (a) is 3-5 hours. In a particular embodiment of the present application, the reaction time of step (a) of the method for preparing the intermediate compound 6 is 5 hours.

[0018] In some embodiments of the present application, the method for preparing the intermediate compound 6 further comprises: (b) further adding a solvent to the reaction system of step (a) and stirring, filtering to obtain the purified intermediate compound 6.

[0019] In some embodiments of the application, the solvent in step (b) of the process for the preparation of intermediate compound 6 is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl-tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO. Preferably, the solvent in step (b) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, n-butanol, acetone, methyl-tert-butyl ether, acetonitrile. Further preferably, the solvent in step (b) is selected from one of methanol, ethanol, acetone, methyl-tert-butyl ether. In a particular embodiment of the application, the solvent in step (b) of the process for the preparation of intermediate compound 6 is selected from ethanol. In another particular embodiment of the application, the solvent in step (b) of the process for the preparation of intermediate compound 6 is selected from acetone.

[0020] In some embodiments of the application, the solvent in step (b) of the process for the preparation of intermediate compound 6 is selected from a mixed solvent of any two solvents of methanol, ethanol, isopropanol, n-butanol, acetone, methyl-tert-butyl ether, acetonitrile; preferably, the solvent in step (b) is selected from a mixed solvent of methanol and methyl-tert-butyl ether, a mixed solvent of acetone and ethanol, a mixed solvent of isopropanol and acetonitrile, a mixed solvent of n-butanol and acetonitrile. Further preferably, the solvent in step (b) is selected from a mixed solvent of methanol and methyl-tert-butyl ether, a mixed solvent of acetone and ethanol. In a particular embodiment of the application, the solvent in step (b) of the process for the preparation of intermediate compound 6 is selected from a mixed solvent of acetone and ethanol.

[0021] In some embodiments of the present application, the solvent in step (b) of the process for preparing the intermediate compound 6 is selected from a mixture of any two solvents selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether, acetonitrile; the volume ratio of the two solvents is 1 : (0.5-10), and the two solvents are interchangeable. For example, in the case of a mixture of ethanol and acetone, the volume ratio of ethanol to acetone can be 1 : (0.5-10), or the volume ratio of acetone to ethanol can be 1 : (0.5-10). Preferably, the volume ratio of the two solvents is 1 : (0.5-6); further preferably, the volume ratio of the two solvents is 1 : (0.5-4); more further preferably, the volume ratio of the two solvents is 1 :0.5, 1 :0.75, 1 : 1, 1 : 1.5, 1 :2, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4.

[0022] In some embodiments of the present application, the solvent in step (b) of the process for preparing the intermediate compound 6 is selected from a mixture of ethanol and acetone; the volume ratio of the ethanol to acetone is 1 : (0.5-10); preferably, the volume ratio of the ethanol to acetone is 1 : (0.5-6); further preferably, the volume ratio of the ethanol to acetone is 1 : (0.5-4); more further preferably, the volume ratio of the ethanol to acetone is 1 :0.5, 1 :0.75, 1 : 1, 1 : 1.5, 1 :2, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4. In a particular embodiment of the present application, the solvent in step (b) of the process for preparing the intermediate compound 6 is selected from a mixture of ethanol and acetone; the volume ratio of the ethanol to acetone is 1 :2.8.

[0023] In some embodiments of the present application, the solvent in step (b) of the preparation method of the intermediate compound 6 is selected from a mixed solvent of methanol and methyl tert-butyl ether; the volume ratio of the methanol and methyl tert-butyl ether in the mixed solvent is 1:(0.5-10); preferably, the volume ratio of the methanol and methyl tert-butyl ether is 1:(0.5-6); further preferably, the volume ratio of the methanol and methyl tert-butyl ether is 1:(0.5-4); more further preferably, the volume ratio of the methanol and methyl tert-butyl ether is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4. In a specific embodiment of the present application, the solvent in step (b) of the preparation method of the intermediate compound 6 is selected from a mixed solvent of methanol and methyl tert-butyl ether, and the volume ratio of the methanol and methyl tert-butyl ether is 1:1.

[0024] In some embodiments of the present application, the volume-to-mass ratio of the solvent in step (b) to the compound of formula II in step (a) is (2-20 mL):1 g; preferably, the volume-to-mass ratio of the solvent in step (b) to the compound of formula II in step (a) is (5-15 mL):1 g; further preferably, the volume-to-mass ratio of the solvent in step (b) to the compound of formula II in step (a) is (10-15 mL):1 g; more further preferably, the volume-to-mass ratio of the solvent in step (b) to the compound of formula II in step (a) is 10 mL:1 g, 10.5 mL:1 g, 11 mL:1 g, 11.5 mL:1 g, 12 mL:1 g, 12.5 mL:1 g, 13 mL:1 g, 13.5 mL:1 g, 14 mL:1 g, 14.5 mL:1 g, 15 mL:1 g. In a specific embodiment of the present application, in the preparation method of the intermediate compound 6, the volume-to-mass ratio of the solvent in step (b) to the compound of formula II in step (a) is 13.5 mL:1 g.

[0025] In some embodiments of the present application, the stirring temperature in step (b) of the preparation method of the intermediate compound 6 is 10-50°C; preferably, the stirring temperature in step (b) is 10-30°C; further preferably, the stirring temperature in step (b) is 20-30°C. In a specific embodiment of the present application, the stirring temperature in step (b) of the preparation method of the intermediate compound 6 is 25-30°C.

[0026] In some embodiments of the present application, the stirring time in step (b) of the process for preparing the intermediate compound 6 is 2 to 20 hours; preferably, the stirring time in step (b) is 5 to 15 hours; further preferably, the stirring time in step (b) is 10 to 15 hours. In a particular embodiment of the present application, the stirring time in step (b) of the process for preparing the intermediate compound 6 is 12 hours.

[0027] In some embodiments of the present application, the process for preparing the intermediate compound 6 further comprises a purification step (c) of the intermediate compound 6: the intermediate compound 6 obtained by filtration in step (b) is further stirred with a solvent, and then stirred after cooling, filtered, to obtain the purified intermediate compound 6.

[0028] In some embodiments of the present application, for the process for preparing the intermediate compound 6, the solvent in the purification step (c) of the intermediate compound 6 is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO; preferably, the solvent in the purification step (c) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether, acetonitrile; further preferably, the solvent in the purification step (c) is selected from one of methanol, ethanol, acetone, methyl tert-butyl ether. In a particular embodiment of the present application, for the process for preparing the intermediate compound 6, the solvent in the purification step (c) is selected from ethanol. In another particular embodiment of the present application, for the process for preparing the intermediate compound 6, the solvent in the purification step (c) is selected from acetone.

[0029] In some embodiments of the present application, for the process for preparing the intermediate compound 6, the solvent in the purification step (c) is selected from a mixed solvent of any two solvents of methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether, acetonitrile; preferably, the solvent in the purification step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of acetone and ethanol, a mixed solvent of isopropanol and acetonitrile, a mixed solvent of n-butanol and acetonitrile; further preferably, the solvent in the purification step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of acetone and ethanol. In a particular embodiment of the present application, for the process for preparing the intermediate compound 6, the solvent in the purification step (c) is selected from a mixed solvent of acetone and ethanol.

[0030] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of any two solvents selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether, acetonitrile; the volume ratio of the two solvents is 1 : (0.5-10), the volume ratio of the two solvents is interchangeable. For example, in the case of a mixture of ethanol and acetone, the volume ratio of ethanol and acetone is 1 : (0.5-10), or the volume ratio of acetone and ethanol is 1 : (0.5-10). Preferably, the volume ratio of the two solvents is 1 : (0.5-6); further preferably, the volume ratio of the two solvents is 1 : (0.5-4); more further preferably, the volume ratio of the two solvents is 1 :0.5, 1 :0.75, 1 :1, 1 :1.5, 1 :2, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4.

[0031] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of ethanol and acetone; the volume ratio of ethanol and acetone is 1 : (0.5-10); preferably, the volume ratio of ethanol and acetone is 1 : (0.5-6); further preferably, the volume ratio of ethanol and acetone is 1 : (0.5-4); more further preferably, the volume ratio of ethanol and acetone is 1 :0.5, 1 :0.75, 1 :1, 1 :1.5, 1 :2, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4. In a particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of ethanol and acetone; the volume ratio of ethanol and acetone is 1 :1. In another particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of ethanol and acetone; the volume ratio of ethanol and acetone is 1 :2.

[0032] In some embodiments of the application, for the process for the preparation of the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of methanol and methyl-tert-butyl ether; the volume ratio of the methanol and methyl-tert-butyl ether is 1 : (0.5-10); preferably, the volume ratio of the methanol and methyl-tert-butyl ether is 1 : (0.5-6); further preferably, the volume ratio of the methanol and methyl-tert-butyl ether is 1 : (0.5-4); more further preferably, the volume ratio of the methanol and methyl-tert-butyl ether is 1 :0.5, 1 :0.75, 1 :1, 1 :1.5, 1 :2, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4. In a particular embodiment of the application, for the process for the preparation of the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of methanol and methyl-tert-butyl ether; the volume ratio of the methanol and methyl-tert-butyl ether is 1 :1. In another particular embodiment of the application, for the process for the preparation of the intermediate compound 6, wherein the solvent in the purification step (c) is selected from a mixture of methanol and methyl-tert-butyl ether; the volume ratio of the methanol and methyl-tert-butyl ether is 1 :1.5.

[0033] In some embodiments of the application, for the process for the preparation of the intermediate compound 6, wherein the volume to mass ratio of the solvent in the purification step (c) to the compound of formula II in step (a) is (2-20 mL):1 g; preferably, the volume to mass ratio of the solvent in the purification step (c) to the compound of formula II in step (a) is (2-10 mL):1 g; further preferably, the volume to mass ratio of the solvent in the purification step (c) to the compound of formula II in step (a) is (2-5 mL):1 g; more further preferably, the volume to mass ratio of the solvent in the purification step (c) to the compound of formula II in step (a) is 2 mL:1 g, 2.5 mL:1 g, 3 mL:1 g, 3.5 mL:1 g, 4 mL:1 g, 4.5 mL:1 g, 5 mL:1 g. In a particular embodiment of the application, for the process for the preparation of the intermediate compound 6, wherein the volume to mass ratio of the solvent in the purification step (c) to the compound of formula II in step (a) is 4 mL:1 g.

[0034] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the heating stirring temperature in the purification step (c) is from 30 °C to 80 °C; preferably, the heating stirring temperature in step (c) is from 30 °C to 50 °C; further preferably, the heating stirring temperature in the purification step (c) is from 40 °C to 50 °C. In a particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the heating stirring temperature in the purification step (c) is from 45 °C to 50 °C.

[0035] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the cooling stirring temperature in the purification step (c) is from 0 °C to 30 °C; preferably, the cooling stirring temperature in step (c) is from 0 °C to 20 °C; further preferably, the cooling stirring temperature in the purification step (c) is from 5 °C to 20 °C. In a particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the cooling stirring temperature in the purification step (c) is from 5 °C to 15 °C.

[0036] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the heating stirring time in the purification step (c) is from 0.5 to 5 hours; preferably, the heating stirring time in the purification step (c) is from 0.5 to 3 hours; further preferably, the heating stirring time in the purification step (c) is from 1 to 3 hours. In a particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the heating stirring time in the purification step (c) is 2 hours.

[0037] In some embodiments of the application, for the process of preparing the intermediate compound 6, wherein the cooling stirring time in the purification step (c) is from 2 to 20 hours; preferably, the cooling stirring time in the purification step (c) is from 2 to 15 hours; further preferably, the cooling stirring time in the purification step (c) is from 5 to 15 hours. In a particular embodiment of the application, for the process of preparing the intermediate compound 6, wherein the cooling stirring time in the purification step (c) is 6 hours.

[0038] In another aspect, the present application provides a process for preparing a compound of formula II, which comprises reacting a compound of formula IV and a compound of formula III in the presence of a reducing agent and a solvent to obtain a compound of formula II.

[0039]

[0040] In some embodiments of the application, the reducing agent in the process for preparing the compound of formula II is selected from formic acid, formic acid / palladium on carbon, ammonium formate / palladium on carbon, hydrazine hydrate / palladium on carbon, Raney nickel / hydrazine hydrate, sodium triacetoxyborohydride, sodium borohydride, FeOOH / hydrazine hydrate, FeOOH / activated carbon / hydrazine hydrate, FeCl3 / hydrazine hydrate, or FeCl3 / activated carbon / hydrazine hydrate; preferably, the reducing agent is selected from sodium triacetoxyborohydride, sodium borohydride, Raney nickel / hydrazine hydrate, or FeOOH / hydrazine hydrate; further preferably, the reducing agent is selected from sodium triacetoxyborohydride or sodium borohydride. In a particular embodiment of the application, the reducing agent in the process for preparing the compound of formula II is sodium triacetoxyborohydride.

[0041] In some embodiments of the application, the reducing agent in the process for preparing the compound of formula II can optionally be used in the presence of a catalyst selected from formic acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, hydrochloric acid, carbonic acid, oxalic acid, hydrofluoric acid, malic acid, benzoic acid, trifluoroacetic acid, hydrogen chloride, guanidinium hydrochloride, pyridine p-toluenesulfonate, titanium tetrachloride, titanium isopropoxide, or zinc chloride; preferably, the catalyst is selected from formic acid, acetic acid, fumaric acid, tartaric acid, maleic acid; further preferably, the catalyst is selected from formic acid or acetic acid. In a particular embodiment of the application, the reducing agent in the process for preparing the compound of formula II is used in the presence of a catalyst selected from acetic acid.

[0042] In some embodiments of the application, the solvent in the process for preparing the compound of formula II is selected from one or more mixed solvents selected from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptane; further preferably, the solvent is selected from one or more mixed solvents selected from dichloromethane, toluene, methanol, methyl tert-butyl ether. In a particular embodiment of the application, the solvent in the process for preparing the compound of formula II is dichloromethane.

[0043] In some embodiments of the present application, the molar ratio of the compound of formula III to the compound of formula IV in the preparation method of the compound of formula II is 1 : (1-3); preferably, the molar ratio of the compound of formula III to the compound of formula IV is 1 : (1-2); further preferably, the molar ratio of the compound of formula III to the compound of formula IV is 1 : 1, 1 : 1.1, 1 : 1.2, 1 : 1.3, 1 : 1.4, 1 : 1.5, 1 : 1.6, 1 : 1.7, 1 : 1.8, 1 : 1.9, 1 : 2. In a particular embodiment of the present application, the molar ratio of the compound of formula III to the compound of formula IV in the preparation method of the compound of formula II is 1 : 1.1.

[0044] In some embodiments of the present application, the molar ratio of the compound of formula III to the reducing agent in the preparation method of the compound of formula II is 1 : (1-5); preferably, the molar ratio of the compound of formula III to the reducing agent is 1 : (1-3); further preferably, the molar ratio of the compound of formula III to the reducing agent is 1 : 1, 1 : 1.5, 1 : 1.6, 1 : 1.7, 1 : 1.8, 1 : 1.9, 1 : 2, 1 : 2.5, 1 : 3. In a particular embodiment of the present application, the molar ratio of the compound of formula III to the reducing agent in the preparation method of the compound of formula II is 1 : 2.

[0045] In some embodiments of the present application, the molar ratio of the compound of formula III to the catalyst in the preparation method of the compound of formula II is 1 : (0.01-1); preferably, the molar ratio of the compound of formula III to the catalyst is 1 : (0.05-1); further preferably, the molar ratio of the compound of formula III to the catalyst is 1 : 0.05, 1 : 0.08, 1 : 0.1, 1 : 0.2, 1 : 0.3, 1 : 0.4, 1 : 0.5, 1 : 0.6, 1 : 0.7, 1 : 0.8, 1 : 0.9, 1 : 1. In a particular embodiment of the present application, the molar ratio of the compound of formula III to the catalyst in the preparation method of the compound of formula II is 1 : 0.2.

[0046] In some embodiments of the application, the molar volume ratio of the compound of formula III to the solvent in the preparation method of the compound of formula II is 1 mmol:(1-10 mL); preferably, the molar volume ratio of the compound of formula III to the solvent is 1 mmol:(1-5 mL); further preferably, the molar volume ratio of the compound of formula III to the solvent is 1 mmol:(2-4 mL); still further preferably, the molar volume ratio of the compound of formula III to the solvent is 1 mmol:2 mL, 1 mmol:2.5 mL, 1 mmol:3 mL, 1 mmol:3.1 mL, 1 mmol:3.2 mL, 1 mmol:3.3 mL, 1 mmol:3.4 mL, 1 mmol:3.5 mL, 1 mmol:3.6 mL, 1 mmol:3.7 mL, 1 mmol:3.8 mL, 1 mmol:3.9 mL, 1 mmol:4 mL. In a particular embodiment of the application, the molar volume ratio of the compound of formula III to the solvent in the preparation method of the compound of formula II is 1 mmol:3.4 mL.

[0047] In some embodiments of the application, the reaction temperature in the preparation method of the compound of formula II is 10-50°C; preferably, the reaction temperature is 10-30°C; further preferably, the reaction temperature is 20-35°C. In a particular embodiment of the application, the reaction temperature in the preparation method of the compound of formula II is 25-35°C.

[0048] In some embodiments of the application, the reaction time in the preparation method of the compound of formula II is 2-24 hours; preferably, the reaction time is 5-20 hours; further preferably, the reaction time is 5-15 hours. In a particular embodiment of the application, the reaction time in the preparation method of the compound of formula II is 10 hours.

[0049] In another aspect, the application provides a preparation method of a compound of formula (I), which comprises: (1) reacting a compound of formula II in the presence of hydrochloric acid and a solvent to obtain an intermediate compound 6; (2) reacting the intermediate compound 6 with a compound 7 in the presence of a solvent and a base to obtain a compound 8; (3) reacting the compound 8 with a compound 9 in the presence of a solvent and an acid to obtain the compound of formula (I).

[0050]

[0051] In the preparation method of the compound of formula (I), the conditions of step (1) are as described above in the preparation method of the intermediate compound 6.

[0052] In some embodiments of the present application, the method for preparing the compound of formula (I) further comprises: (1') further adding a solvent to the reaction system of step (1) and stirring, filtering to obtain the purified intermediate compound 6. Wherein, the conditions of step (1') are as described in the above method for preparing the intermediate compound 6, step (b).

[0053] In some embodiments of the present application, the method for preparing the compound of formula (I) further comprises a purification step (1") of the intermediate compound 6: further heating and stirring the intermediate compound 6 obtained by filtering step (1'), then cooling and stirring, filtering to obtain the purified intermediate compound 6. Wherein, the conditions of the purification step (1") of the intermediate compound 6 are as described in the above method for preparing the intermediate compound 6, step (c).

[0054] In some embodiments of the present application, the solvent in step (2) of the method for preparing the compound of formula (I) is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent in step (2) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile; further preferably, the solvent in step (2) is selected from one of methanol, ethanol, acetonitrile; in a specific embodiment of the present application, the solvent in step (2) of the method for preparing the compound of formula (I) is acetonitrile.

[0055] In some embodiments of the present application, the base in step (2) of the method for preparing the compound of formula (I) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, triethylamine, pyridine, triethanolamine, sodium hydroxide, potassium hydroxide or calcium hydroxide; preferably, the base in step (2) is selected from one or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide or calcium hydroxide; further preferably, the base in step (2) is selected from one of sodium carbonate, potassium carbonate or calcium carbonate; in a specific embodiment of the present application, the base in step (2) of the method for preparing the compound of formula (I) is sodium carbonate.

[0056] In some embodiments of the present application, in step (2) of the method for preparing the compound of formula (I), the molar ratio of intermediate compound 6 to compound 7 is 1:(1-3); preferably, the molar ratio of intermediate compound 6 to compound 7 is 1:(1-1.5); further preferably, the molar ratio of intermediate compound 6 to compound 7 is 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5. In a particular embodiment of the present application, in step (2) of the method for preparing the compound of formula (I), the molar ratio of intermediate compound 6 to compound 7 is 1:1.05.

[0057] In some embodiments of the present application, in step (2) of the method for preparing the compound of formula (I), the molar ratio of intermediate compound 6 to base is 1:(1-8); preferably, the molar ratio of intermediate compound 6 to base is 1:(1-5); further preferably, the molar ratio of intermediate compound 6 to base is 1:1, 1:2, 1:3, 1:4, 1:5. In a particular embodiment of the present application, in step (2) of the method for preparing the compound of formula (I), the molar ratio of intermediate compound 6 to base is 1:3.

[0058] In some embodiments of the present application, in step (2) of the method for preparing the compound of formula (I), the reaction temperature is 50-120°C; preferably, the reaction temperature is 80-120°C; further preferably, the reaction temperature is 80-100°C. In a particular embodiment of the present application, in step (2) of the method for preparing the compound of formula (I), the reaction temperature is 80-90°C.

[0059] In some embodiments of the present application, in step (2) of the method for preparing the compound of formula (I), the reaction time is 2-24 hours; preferably, the reaction time is 10-24 hours; further preferably, the reaction time is 10-20 hours. In a particular embodiment of the present application, in step (2) of the method for preparing the compound of formula (I), the reaction time is 16 hours.

[0060] In some embodiments of the present application, in step (2) of the method for preparing the compound of formula (I), step (2) further comprises: (2') stirring the compound 8 obtained in step (2) with a solvent, filtering, washing the filter cake with a beating solvent, filtering, and drying the filter cake to obtain refined compound 8.

[0061] In some embodiments of the application, the solvent in step (2') of the process for the preparation of the compound of formula (I) is selected from one or more mixed solvents of water, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile; preferably, the solvent in step (2') is selected from water.

[0062] In some embodiments of the application, the beating solvent in step (2') of the process for the preparation of the compound of formula (I) is selected from one or more mixed solvents of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane; preferably, the beating solvent in step (2') is selected from methyl tert-butyl ether.

[0063] In some embodiments of the application, the solvent in step (3) of the process for the preparation of the compound of formula (I) is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent in step (3) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetonitrile; further preferably, the solvent in step (3) is selected from one of methanol, ethanol, 1,4-dioxane, acetonitrile; in a particular embodiment of the application, the solvent in step (3) of the process for the preparation of the compound of formula (I) is selected from 1,4-dioxane.

[0064] In some embodiments of the application, the acid in step (3) of the process for the preparation of the compound of formula (I) is selected from one or several of p-toluenesulfonic acid, trifluoroacetic acid, triflic acid, methanesulfonic acid, hydrofluoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hydrochloric acid, phosphoric acid or sulfuric acid; preferably, the acid in step (3) is selected from one or several of p-toluenesulfonic acid, trifluoroacetic acid, triflic acid or methanesulfonic acid; further preferably, the acid in step (3) is selected from one of p-toluenesulfonic acid, trifluoroacetic acid; in a particular embodiment of the application, the acid in step (3) of the process for the preparation of the compound of formula (I) is selected from p-toluenesulfonic acid.

[0065] In some embodiments of the present application, the molar ratio of compound 8 to compound 9 in step (3) of the preparation method of the compound of formula (I) is 1 : (1-3); preferably, the molar ratio of compound 8 to compound 9 is 1 : (1-1.5); further preferably, the molar ratio of compound 8 to compound 9 is 1 : 1, 1 : 1.05, 1 : 1.1, 1 : 1.15, 1 : 1.2, 1 : 1.25, 1 : 1.3, 1 : 1.35, 1 : 1.4, 1 : 1.45, 1 : 1.5. In a particular embodiment of the present application, the molar ratio of compound 8 to compound 9 in step (3) of the preparation method of the compound of formula (I) is 1 : 1.05.

[0066] In some embodiments of the present application, the molar ratio of compound 8 to acid in step (3) of the preparation method of the compound of formula (I) is 1 : (1-8); preferably, the molar ratio of compound 8 to acid is 1 : (1-5); further preferably, the molar ratio of compound 8 to acid is 1 : 1, 1 : 2, 1 : 3, 1 : 4, 1 : 5. In a particular embodiment of the present application, the molar ratio of compound 8 to acid in step (3) of the preparation method of the compound of formula (I) is 1 : 3.

[0067] In some embodiments of the present application, the reaction temperature in step (3) of the preparation method of the compound of formula (I) is 50-120 °C; preferably, the reaction temperature is 80-120 °C; further preferably, the reaction temperature is 90-110 °C. In a particular embodiment of the present application, the reaction temperature in step (3) of the preparation method of the compound of formula (I) is 95-105 °C.

[0068] In some embodiments of the present application, the reaction time in step (3) of the preparation method of the compound of formula (I) is 2-24 hours; preferably, the reaction time is 10-24 hours; further preferably, the reaction time is 10-20 hours. In a particular embodiment of the present application, the reaction time in step (3) of the preparation method of the compound of formula (I) is 16 hours.

[0069] In another aspect, the present application provides a preparation method of a compound of formula (I), which comprises: (i) reacting a compound of formula IV and a compound of formula III in the presence of a reducing agent and a solvent to obtain a compound of formula II; (ii) reacting the compound of formula II in the presence of hydrochloric acid and a solvent to obtain an intermediate compound 6; (iii) reacting the intermediate compound 6 with a compound 7 in the presence of a solvent and a base to obtain a compound 8; (iv) reacting the compound 8 and a compound 9 in the presence of a solvent and an acid to obtain the compound of formula (I).

[0070]

[0071] wherein the conditions of step (i), step (ii), step (iii) and step (iv) in the preparation method of the compound of formula (I) are as described in the preparation method of the compound of formula II, the preparation method of intermediate compound 6 step (a), the preparation method of the compound of formula (I) step (2) and the preparation method of the compound of formula (I) step (3) respectively.

[0072] In some embodiments of the present application, the preparation method of the compound of formula (I) further comprises: (ii’) further adding solvent stirring to the reaction system of step (ii), filtering to obtain purified intermediate compound 6. Wherein the conditions of step (ii’) are as described in step (b) of the preparation method of intermediate compound 6 above.

[0073] In some embodiments of the present application, the preparation method of the compound of formula (I) further comprises a refining step (ii”) of intermediate compound 6: further heating and stirring intermediate compound 6 obtained by filtering step (ii’) with solvent, then cooling and stirring, filtering to obtain refined intermediate compound 6. Wherein the conditions of the refining step (ii”) of intermediate compound 6 are as described in step (c) of the preparation method of intermediate compound 6 above.

[0074] In another aspect, the present application also provides a preparation method of a compound of formula IV, which comprises: reacting a compound of formula VI and a compound of formula V in the presence of a solvent to obtain a compound of formula IV.

[0075]

[0076] In some embodiments of the present application, the solvent in the preparation method of the compound of formula IV is selected from one or more mixed solvents of water, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent is selected from one or more mixed solvents of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile; further preferably, the solvent is selected from one or more mixed solvents of water, methanol, ethanol or isopropanol. In a specific embodiment of the present application, the solvent in the preparation method of the compound of formula IV is selected from water.

[0077] In some embodiments of the present application, the molar ratio of the compound of formula VI to the compound of formula V in the preparation method of the compound of formula IV is 1:(1-3); preferably, the molar ratio of the compound of formula VI to the compound of formula V is 1:(1-1.5); further preferably, the molar ratio of the compound of formula VI to the compound of formula V is 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5. In a particular embodiment of the present application, the molar ratio of the compound of formula VI to the compound of formula V in the preparation method of the compound of formula IV is 1:1.1.

[0078] In some embodiments of the present application, the molar volume ratio of the compound of formula VI to the solvent in the preparation method of the compound of formula IV is (1-5 mmol):1 mL; preferably, the molar volume ratio of the compound of formula VI to the solvent is (2-4 mmol):1 mL; further preferably, the molar volume ratio of the compound of formula VI to the solvent is 2 mmol:1 mL, 2.5 mmol:1 mL, 3 mmol:1 mL, 3.5 mmol:1 mL, 4 mmol:1 mL. In a particular embodiment of the present application, the molar volume ratio of the compound of formula VI to the solvent in the preparation method of the compound of formula IV is 3 mmol:1 mL.

[0079] In some embodiments of the present application, the reaction temperature in the preparation method of the compound of formula IV is 10-50°C; preferably, the reaction temperature is 10-40°C; further preferably, the reaction temperature is 20-40°C. In a particular embodiment of the present application, the reaction temperature in the preparation method of the compound of formula IV is 20-30°C.

[0080] In some embodiments of the present application, the reaction time in the preparation method of the compound of formula IV is 2-24 hours; preferably, the reaction time is 10-24 hours; further preferably, the reaction time is 10-20 hours. In a particular embodiment of the present application, the reaction time in the preparation method of the compound of formula IV is 12 hours.

[0081] The present application also provides the use of a preparation method of an intermediate compound 6 for preparing the compound of formula (I), wherein the preparation method of the intermediate compound 6 comprises: (a) reacting the compound of formula II in the presence of hydrochloric acid and a solvent to obtain the intermediate compound 6.

[0082]

[0083] wherein the conditions of step (a) are as described above.

[0084] The application also provides a method for preparing the compound of formula (I), which comprises: preparing the intermediate compound 6 from the compound of formula II according to the above method of the application, and further preparing the compound of formula (I).

[0085] The method for preparing the compound of formula (I) further comprises the following steps: preparing the compound of formula II from the compound of formula IV and the compound of formula III according to the above method of the application, and / or preparing the compound of formula IV from the compound of formula VI and the compound of formula V according to the above method of the application.

[0086] Technical effects

[0087] The preparation method of the application, compared with the known method for separating the trans isomer by liquid phase or directly using the expensive trans isomer raw material, can directly prepare the high-purity trans isomer intermediate compound 6 after the reaction of the compound of formula II under the condition of hydrochloric acid and a specific solvent, and the obtained product is convenient for subsequent further purification, and has the advantages of mild reaction condition, short reaction step, short reaction time, simple post-treatment operation, high isomer purity, etc., and is very suitable for industrial production.

[0088] Terms and definitions

[0089] The "DMF" described in the application is N,N-dimethylformamide.

[0090] The "DMAC" described in the application is N,N-dimethylacetamide.

[0091] The "DMSO" described in the application is dimethyl sulfoxide.

[0092] The "MTBE" described in the application is methyl tert-butyl ether.

[0093] The acids and bases described in the application include anhydrous forms and hydrate forms.

[0094] The term "hydrochloric acid" includes hydrogen chloride gas and hydrogen chloride solution, which includes aqueous solution and organic solvent solution.

[0095] The term "concentrated hydrochloric acid" refers to an aqueous hydrogen chloride solution with a hydrogen chloride mass fraction of more than 20%. For example, the concentration of the concentrated hydrochloric acid can be 36%-38%, i.e. an aqueous hydrogen chloride solution with a hydrogen chloride mass fraction of 36%-38%.

[0096] The compound of formula VI, the compound of formula V, the compound of formula IV, the compound of formula III, compound 7, and compound 9 described in the application can be obtained by commercial purchase.

[0097] The compound of formula IV described in the application can also be prepared from the compound of formula VI and the compound of formula V in the presence of a solvent by the above preparation method of the compound of formula IV.

[0098] Compounds 7 and 9 described herein can also be prepared by the methods disclosed in WO2020001449.

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, publications, and other documents referenced herein are hereby incorporated by reference in their entirety. In the event of a conflict in terminology, practice or otherwise between the definitions in this section and those contained in any such documents, the definitions in this section control. If a URL or other such identifier or address is provided herein, it is understood that such identifier might change, and the Internet might move or delete the specific information from the location, but the appropriate information can still be found by searching the Internet or other appropriate resource. Citation of a reference herein indicates that the information was available and publicly disseminated prior to the filing date of this document.

[0100] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural, unless specifically stated otherwise. It should also be noted that, as used in the specification and the appended claims, the singular form "a," "an" and "the" include plural references unless the context clearly dictates otherwise. It should also be noted that, as used in the specification and the appended claims, the term "or" is generally used in the sense of "and / or" unless the context clearly dictates otherwise. In addition, the use of the term "including" and other forms such as "include," "includes," and "including" is not limiting.

[0101] All reagents used in this application are commercially available and used without further purification. DETAILED DESCRIPTION

[0102] The application is described in detail below by way of Examples, but it is not meant to be limited by any of the Examples. The application has been described in detail by specific reference to embodiments thereof, which disclose specific embodiments. Various modifications and changes can be made thereto by those skilled in the art without departing from the spirit and scope of the application as set forth in the claims.

[0103] Example 1: Preparation of compound of formula IV

[0104]

[0105] In a 100 mL reaction flask, 5.0 g of the compound of formula VI, 20 mL of water, and 35-40 °C stirring were added to dissolve the solution, and the temperature was reduced to 25 °C after dissolution. 5.8 g of the compound of formula V was added, and 20-30 °C reaction was carried out for 12 hours. After the reaction was completed, the pH was adjusted to 1 with concentrated hydrochloric acid, and it was washed with dichloromethane three times (3 x 6 mL). The aqueous phase was adjusted to pH 9.8 with a 30 wt% sodium hydroxide solution, and 5.0 g of sodium chloride was added to the aqueous phase and stirred to dissolve. The organic phase was extracted with dichloromethane three times (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was combined and concentrated under reduced pressure to obtain 4.1 g of the compound of formula IV.

[0106] ESI-MS: m / z = 145.1 [M+H] +

[0107] Example 2: Preparation of the compound of formula II

[0108]

[0109] In a 1 L reaction flask, 30.0 g of the compound of formula III, 21.9 g of the compound of formula IV, 1.7 g of acetic acid, and 480 mL of dichloromethane were added and stirred at 25-35 °C, and then 59.6 g of sodium triacetoxyborohydride (divided into two times, and added every half an hour) was added, and stirred at 25-35 °C for 10 hours. TLC monitoring (dichloromethane:methanol = 10:1, molybdenum phosphate coloration) was carried out until the starting material was completely reacted. The reaction solution was adjusted to pH 7.5 with a 5 N sodium hydroxide solution, filtered, and the filtrate was washed with a 5% sodium carbonate solution twice (2 x 300 mL), and the organic phase was collected and used as it was. The aqueous phases were combined, extracted with dichloromethane once (300 mL), and all the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 30 ± 5 °C until dryness. The concentrate was washed with 360 mL of a n-heptane:methyl tert-butyl ether = 5:1 mixed solvent, stirred for 12 hours, filtered, and the filtrate was dried under reduced pressure at 45 ± 5 °C for 6 hours to obtain 41.1 g of the compound of formula II, cis isomer:trans isomer = 1.09:1.

[0110] NMR: 1 H NMR (400 MHz, CDCl3) δ 4.37 (s, 1H), 3.69 (s, 3H), 3.37-3.50 (m, 5H), 2.50 (s, 4H), 2.22-2.27 (m, 1H), 2.06 (d, J = 11.60 Hz, 2H), 1.87 (d, J = 12.40 Hz, 2H), 1.44 (s, 9H), 1.28-1.38 (m, 2H), 1.09-1.13 (m, 2H).

[0111] Example 3-1: Preparation of the intermediate compound 6

[0112]

[0113] Into a 100 mL reaction flask, 41.0 g of the compound of formula II, 205 mL of acetone, and 59.2 g of concentrated hydrochloric acid were added and stirred at 25-30°C until the reaction was completed. Then, 410 mL of acetone and 144 mL of ethanol were added and stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with 169 mL of a mixed solvent of ethanol / acetone = 1:1. The mixed solvent was heated at 45-50°C for 2 hours, and then slowly cooled to 5-15°C. The mixture was stirred for 6 hours or more, and then filtered. The filter cake was dried at 50±5°C under reduced pressure for 6 hours to obtain 16.1 g of the intermediate compound 6 having a purity of 99.08%.

[0114] Hydrogen spectrum: 1 H NMR (400 MHz, CD3OD) δ 4.27-4.30 (m, 2H), 3.73 (s, 3H), 3.55-3.57 (m, 2H), 3.35-3.39 (m, 3H), 3.16-3.19 (m, 3H), 2.21-2.33 (m, 4H), 1.73-1.77 (m, 2H), 1.55-1.59 (m, 2H).

[0115] The method of preparing the intermediate compound 6 according to Example 3-1 was repeated, except that the mixed solvent was replaced with the solvent in Table 1, wherein the solvent was a mixed solvent of ethanol / acetone = 1:1.

[0116] Table 1

[0117] Beating solvent Intermediate compound 6 purity Ethanol 99.22％ Acetone 95.45％ Ethanol:acetone = 1 :2 98.28％ Ethanol:acetone = 1 :3 97.24％ Ethanol:acetone = 1 :4 96.26％ Methanol:MTBE = 1 :0.5 94.91％ Methanol:MTBE = 1 :0.75 92.40％ Methanol:MTBE = 1 :1 96.58％ Methanol:MTBE = 1 :1.5 96.35％ Methanol:MTBE = 1 :2 95.24％ Methanol:MTBE = 1 :2 (methanol added first, 30 minutes apart from MTBE) 97.13％

[0118] Example 3-2: Preparation of intermediate compound 6

[0119]

[0120] Into a 100 mL reaction flask, 41.0 g of the compound of formula II, 205 mL of acetone, and 59.2 g of concentrated hydrochloric acid were added and stirred at 25-30°C until the reaction was completed. Then, 410 mL of acetone and 144 mL of ethanol were added and stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with 169 mL of a mixed solvent of ethanol / acetone = 1:1. The mixed solvent was heated at 45-50°C for 2 hours, and then slowly cooled to 5-15°C. The mixture was stirred for 6 hours or more, and then filtered. The filter cake was dried at 50±5°C under reduced pressure for 6 hours to obtain 16.1 g of the intermediate compound 6 having a purity of 99.08%.

[0121] Example 3-3: Preparation of intermediate compound 6

[0122]

[0123] In a 100 mL reaction bottle, 41.0 g of the compound of formula II, 205 mL of acetone, and 25-30 °C were stirred uniformly, 59.2 g of concentrated hydrochloric acid with a concentration of 36%-38% was added, and 25-30 °C was stirred for 5 hours. TLC detection (dichloromethane:methanol = 10:1, phosphomolybdic acid coloration) was performed until the raw material was completely reacted. 410 mL of acetone and 144 mL of ethanol were added, and 12 hours of stirring was performed at room temperature. Filtration was performed, the filter cake was slurried with 169 mL of ethanol / acetone = 2:1 mixed solvent, heated at 45-50 °C for 2 hours, slowly cooled to 5-15 °C, stirred for 6 hours or more, and filtration was performed. The filter cake was dried under reduced pressure at 50±5 °C for 6 hours, and 14.7 g of the intermediate compound 6 was obtained with a purity of 98.28%.

[0124] Example 4: Preparation of the compound of formula (I)

[0125]

[0126] The compound of formula IV was prepared according to Example 1;

[0127] The compound of formula II was prepared according to Example 2;

[0128] The intermediate compound 6 was prepared according to Example 3;

[0129] Preparation of compound 8:

[0130] In a reaction tank, 53 L of acetonitrile, 2.65 kg of compound 7, and 3.59 kg of intermediate compound 6 were stirred, 3.83 kg of anhydrous sodium carbonate was added in batches, the temperature was increased to 80-90 °C, and stirring was performed for 16 hours. TLC tracking was performed on the sample to monitor the reaction endpoint. After the reaction was completed, the temperature was decreased to 20-30 °C, purified water was added to the reaction tank, and stirring was performed for 1 hour. Filtration was performed, the filter cake was washed with methyl tert-butyl ether at 20-30 °C, filtration was performed, and the filter cake was dried at 45±5 °C to obtain 4.11 kg of compound 8.

[0131] Hydrogen spectrum: 1H NMR (400 MHz, DMSO-d6) δ 7.00 (d, J = 8.00 Hz, 1H), 3.98-4.17 (m, 1H), 3.58 (s, 3H), 3.31-3.29 (m, 4H), 2.82-2.75 (m, 3H), 2.47 (s, 4H), 2.37-2.30 (m, 1H), 2.04-1.94 (m, 2H), 1.83 (d, J = 12.00 Hz, 2H), 1.65-1.52 (m, 2H), 1.44-1.31 (m, 2H). ESI-MS: m / z = 425.2 [M+H]+.

[0132] Preparation of the compound of formula (I):

[0133] In the reaction tank, 1,4-dioxane 40.7 L, 4.07 kg of compound 8, 1.68 kg of compound 9, and p-toluenesulfonic acid monohydrate 5.47 kg were added, and the temperature was raised to 95-105°C. After stirring for 16 hours, sampling TLC was used to track and monitor the reaction to the end point. After the reaction was completed, the temperature was lowered to 30-40°C, and purified water 40.7 L and methyl tert-butyl ether 40.7 L were added to the reaction tank and stirred for 15 minutes, and then separated. The aqueous phase was extracted with methyl tert-butyl ether, and then separated. The aqueous phase was added with 1 mol / L sodium hydroxide solution to pH ≈ 11-13, and then filtered. The filter cake was washed with 0.1 mol / L sodium hydroxide solution by stirring, and then filtered. The filter cake was washed with purified water by stirring for 4 times, and then filtered. The filter cake was washed with acetonitrile aqueous solution by stirring, and then filtered. The filter cake was dried at 45±5°C to obtain 4.60 kg of the compound of formula (I).

[0134] Hydrogen spectrum: 1H NMR (400 MHz, DMSO-d6) δ 7.76 (brs, 1H), δ 7.59 (brs, 1H), δ 4.38 (m, 1H), δ 3.92 (m, 1H), δ 3.34 (m, 1H), δ 4.24 (m, 2H), δ 3.51 (m, 2H), δ 3.24 (m, 2H), δ 3.13 (m, 2H), δ 4.02 (m, 2H), δ 3.57 (m, 2H), δ 2.01 (m, 2H), δ 1.92 (m, 2H), δ 2.21 (m, 2H), δ 2.19 (m, 4H), δ 1.58 (m, 2H), δ 3.67 (s, 3H), δ 2.54 (s, 3H). ESI-MS: m / z = 628.62 [M+H] + .

[0135] Example 5: Preparation of the hydrochloride salt of the compound of formula (I)

[0136]

[0137] In the reaction tank, 1,4-dioxane 40.7 L, 4.07 kg of compound 8, 1.68 kg of compound 9, and p-toluenesulfonic acid monohydrate 5.47 kg were added, and the temperature was raised to 95-105°C. After stirring for 16 hours, sampling TLC was used to track and monitor the reaction to the end point. After the reaction was completed, the temperature was lowered to 30-40°C, and purified water 40.7 L and methyl tert-butyl ether 40.7 L were added to the reaction tank and stirred for 15 minutes, and then separated. The aqueous phase was extracted with methyl tert-butyl ether, and then separated. The aqueous phase was added with 1 mol / L sodium hydroxide solution to pH ≈ 11-13, and then filtered. The filter cake was washed with 0.1 mol / L sodium hydroxide solution by stirring, and then filtered. The filter cake was washed with purified water by stirring for 4 times, and then filtered. The filter cake was washed with acetonitrile aqueous solution by stirring, and then filtered. The filter cake was dried at 45±5°C to obtain 4.60 kg of the compound of formula (I).

[0137] In the reaction tank, 1,4-dioxane 40.7 L, 4.07 kg of compound 8, 1.68 kg of compound 9, and p-toluenesulfonic acid monohydrate 5.47 kg were added, and the temperature was raised to 95-105°C. After stirring for 16 hours, sampling TLC was used to track and monitor the reaction to the end point. After the reaction was completed, the temperature was lowered to 30-40°C, and purified water 40.7 L and methyl tert-butyl ether 40.7 L were added to the reaction tank and stirred for 15 minutes, and then separated. The aqueous phase was extracted with methyl tert-butyl ether, and then separated. The aqueous phase was added with 1 mol / L sodium hydroxide solution to pH ≈ 11-13, and then filtered. The filter cake was washed with 0.1 mol / L sodium hydroxide solution by stirring, and then filtered. The filter cake was washed with purified water by stirring for 4 times, and then filtered. The filter cake was washed with acetonitrile aqueous solution by stirring, and then filtered. The filter cake was dried at 45±5°C to obtain 4.60 kg of the compound of formula (I).

Claims

1. A method of preparing an intermediate compound 6, comprising: (i) the compound of formula IV and the compound of formula III are reacted in the presence of a reducing agent and a solvent to obtain the compound of formula II; (ii) the compound of formula II is reacted in the presence of hydrochloric acid and a solvent to obtain the intermediate compound 6; the reducing agent in step (i) is selected from sodium triacetoxyborohydride, and the solvent is selected from dichloromethane; the solvent in step (ii) is selected from acetone; the hydrochloric acid in step (ii) is selected from concentrated hydrochloric acid, a hydrochloric acid / ethyl acetate solution, a hydrochloric acid / acetone solution, a hydrochloric acid / methanol solution, a hydrochloric acid / ethanol solution, a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / methanol solution, a hydrogen chloride / ethanol solution, or a hydrogen chloride / dioxane solution.

2. The method for preparing the intermediate compound 6 according to claim 1, wherein the molar ratio of the compound of formula II to the hydrochloric acid in step (ii) is 1:1-10.

3. The method for preparing the intermediate compound 6 according to claim 1, wherein the molar volume ratio of the compound of formula II to the solvent in step (ii) is 1 mmol: 1-5 mL.

4. The method for preparing the intermediate compound 6 according to claim 1, wherein further comprising step (b) of further adding a solvent to the reaction system of step (ii) and stirring, filtering to obtain the purified intermediate compound 6.

5. The method for preparing the intermediate compound 6 according to claim 4, wherein the solvent in step (b) is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO.

6. The method for preparing the intermediate compound 6 according to claim 4, wherein the solvent in step (b) is selected from a mixed solvent of any two solvents of methanol, ethanol, isopropanol, n-butanol, acetone, and methyl tert-butyl ether.

7. The method for preparing the intermediate compound 6 according to claim 4, wherein the solvent in step (b) is selected from a mixed solvent of ethanol and acetone; the volume ratio of the mixed solvent of ethanol and acetone is 1:0.5-10.

8. The method for preparing the intermediate compound 6 according to claim 4, wherein the solvent in step (b) is selected from a mixed solvent of methanol and methyl tert-butyl ether; the volume ratio of the mixed solvent of methanol and methyl tert-butyl ether is 1:0.5-10.

9. The method for preparing the intermediate compound 6 according to claim 4, wherein the volume / mass ratio of the solvent in step (b) to the compound of formula II in step (ii) is 2-20 mL:1 g.

10. The method for preparing the intermediate compound 6 according to claim 4, wherein further comprising a refining step (c) of the intermediate compound 6: further heating and stirring the intermediate compound 6 obtained by filtering in step (b) with a solvent, then cooling and stirring, filtering to obtain the refined intermediate compound 6.

11. The process of claim 10, wherein the solvent of the purification step (c) of the intermediate compound 6 is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO.

12. The process of claim 10, wherein the solvent of the purification step (c) is selected from a mixed solvent of ethanol and acetone; the volume ratio of the mixed solvent of ethanol and acetone is 1:0.5-10.

13. The process of claim 10, wherein the solvent of the purification step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether; the volume ratio of the mixed solvent of methanol and methyl tert-butyl ether is 1:0.5-10.

14. A process for the preparation of intermediate compound 6 according to claim 1, wherein the process for the preparation of the compound of formula IV comprises: The compound of formula VI and the compound of formula V are reacted in the presence of a solvent to obtain the compound of formula IV; 15. A method of preparing a compound of formula (I), said method comprising: (i) the compound of formula IV and the compound of formula III are reacted in the presence of a reducing agent and a solvent to obtain the compound of formula II; (ii) the compound of formula II is reacted in the presence of hydrochloric acid and a solvent to obtain the intermediate compound 6; (iii) the intermediate compound 6 is reacted with the compound 7 in the presence of a solvent and a base to obtain the compound 8; (iv) the compound 8 and the compound 9 are reacted in the presence of a solvent and an acid to obtain the compound of formula (I); wherein, in the process of preparing the compound of formula (I), step (i) is as described in claim 1, step (ii) is as described in any one of claims 1-13; the solvent of step (iii) is acetonitrile, and the base is selected from sodium carbonate; the solvent of step (iv) is 1,4-dioxane, and the acid is selected from p-toluenesulfonic acid.

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