WO2023104195A1 - 一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法 - Google Patents

一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法 Download PDF

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WO2023104195A1
WO2023104195A1 PCT/CN2022/138020 CN2022138020W WO2023104195A1 WO 2023104195 A1 WO2023104195 A1 WO 2023104195A1 CN 2022138020 W CN2022138020 W CN 2022138020W WO 2023104195 A1 WO2023104195 A1 WO 2023104195A1
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compound
preparation
formula
solvent
intermediate compound
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PCT/CN2022/138020
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English (en)
French (fr)
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王笃政
郭猛
侯永胜
宋永辉
程瑛
孙利明
江竹莲
金美红
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正大天晴药业集团股份有限公司
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Priority to CN202280081494.3A priority Critical patent/CN118339161A/zh
Publication of WO2023104195A1 publication Critical patent/WO2023104195A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This application belongs to the field of medicine and chemical industry, and relates to a preparation method of isothiazolo[5,4-d]pyrimidine IRAK4 inhibitors, specifically to the compound of formula (I): 4-((1R,4R)-4-(( 3-Methyl-6-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)isothiazolo[5,4-d]pyrimidine-4- Base) amino) cyclohexyl) piperazine-1-carboxylate methyl ester and its intermediate compound 6: the preparation method of 4-((1R,4R)-4-aminocyclohexyl) piperazine-1-carboxylate methyl ester .
  • Interleukin-1 receptor kinase 4 is a serine/threonine-specific protein kinase, a member of the tyrosine kinase (TLK) family, and a receptor for interleukin-1, interleukin-18, and interleukin-33 A key node in the innate immune response involving Toll-like receptors.
  • IRAK4 After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they are recruited to form MyD88:IRAK4:IRAK1/2 multiprotein complexes, leading to phosphorylation of IRAK1/2, mediating a series of downstream signal transduction, thereby activating p38 and JNK and NF-kB signaling pathways, ultimately leading to the expression of pro-inflammatory cytokines.
  • Clinicopathological studies have shown that individuals with IRAK4 mutations have protective effects against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal and individuals survive into adulthood with a reduced risk of infection with age. Therefore, IRAK4 has become an important class of therapeutic targets and has attracted extensive research and development interest.
  • WO2021147968 discloses a compound of formula (I), and discloses a preparation method of the compound of formula (I), the preparation method is shown in the following route:
  • intermediate compound 6 is the key intermediate prepared by the compound of formula (I), but in the preparation method of intermediate compound 6, the expensive trans isomer compound 2 is introduced as the starting material, and the metal palladium catalyst is introduced simultaneously Benzyl protection, and the preparation route of this method is long, and the yield is low, so it is not suitable for industrial production.
  • the present application provides a preparation method of intermediate compound 6, the preparation method comprising: (a) reacting the compound of formula II in the presence of hydrochloric acid and a solvent to obtain intermediate compound 6.
  • the hydrochloric acid described in step (a) of the preparation method of 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 the two.
  • the hydrochloric acid described in step (a) is a solution of hydrogen chloride, including aqueous solution and organic solvent solution or a mixed solution thereof.
  • the hydrochloric acid described in the step (a) of the preparation method of the intermediate compound 6 is selected from hydrochloric acid/water solution, hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, hydrochloric acid/acetone solution , hydrochloric acid/ethanol solution, or hydrochloric acid/dioxane solution.
  • the hydrochloric acid described in the step (a) of the preparation method of the intermediate compound 6 is selected from the mixed solution of hydrochloric acid/water solution, hydrogen chloride/methanol and water, 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.
  • the hydrochloric acid described in step (a) of the preparation method of the intermediate compound 6 is selected from concentrated hydrochloric acid, concentrated hydrochloric acid/methanol solution, concentrated hydrochloric acid/ethyl acetate solution, concentrated hydrochloric acid/acetone solution, concentrated hydrochloric acid/ethanol solution, hydrogen chloride/ethyl acetate solution, hydrogen chloride/methanol solution, hydrogen chloride/ethanol solution or hydrogen chloride/dioxane solution.
  • the hydrochloric acid described in step (a) of the preparation method of the intermediate compound 6 is selected from concentrated hydrochloric acid, hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, hydrochloric acid/acetone solution, Hydrochloric acid/ethanol solution, hydrogen chloride/ethyl acetate solution, hydrogen chloride/methanol solution, hydrogen chloride/ethanol solution or hydrogen chloride/dioxane solution.
  • the hydrochloric acid described in step (a) is selected from 30%-60% concentrated hydrochloric acid; or, the hydrochloric acid described in step (a) is selected from 1-10mol/L hydrogen chloride solution, including the organic solvent solution of hydrogen chloride , or a mixed solution of hydrogen chloride in an organic solvent and water.
  • the hydrochloric acid described in step (a) is selected from 30%-60% concentrated hydrochloric acid, or selected from 1-10mol/L hydrochloric acid/methanol solution, hydrochloric acid/ethyl acetate solution, hydrochloric acid/acetone solution, hydrochloric acid /ethanol solution, hydrogen chloride/ethyl acetate solution, hydrogen chloride/methanol solution, hydrogen chloride/ethanol solution or hydrogen chloride/dioxane solution.
  • the hydrochloric acid in step (a) is selected from 30%-40% concentrated hydrochloric acid.
  • the hydrochloric acid in step (a) is selected from 36%-38% concentrated hydrochloric acid.
  • the hydrochloric acid in the step (a) of the preparation method of the intermediate compound 6 is selected from 37% concentrated hydrochloric acid.
  • the solvent described in step (a) of the preparation method of the intermediate compound 6 is selected from one of ethanol, acetone, and methyl tert-butyl ether. In a specific embodiment of the present application, the solvent described in the step (a) of the preparation method of the intermediate compound 6 is selected from acetone.
  • the molar ratio of the compound of formula II to hydrochloric acid in the step (a) of the preparation method of the intermediate compound 6 is 1:(1 ⁇ 10); preferably, the formula in step (a) The molar ratio of compound II to hydrochloric acid is 1:(1-5); further preferably, the molar ratio of compound II to hydrochloric acid in step (a) is 1:(3-5). Even more 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 specific embodiment of the present application, the molar ratio of the compound of formula II to hydrochloric acid in step (a) of the preparation method of the intermediate compound 6 is 1:5.
  • the molar ratio of the compound of formula II to hydrogen chloride in the step (a) of the preparation method of the intermediate compound 6 is 1:(1 ⁇ 10); preferably, the formula in step (a) The molar ratio of compound II to hydrogen chloride is 1:(1-5); further preferably, the molar ratio of compound II to hydrogen chloride in step (a) is 1:(3-5). Even more 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 specific embodiment of the present application, the molar ratio of the compound of formula II to hydrogen chloride in step (a) of the preparation method of the intermediate compound 6 is 1:5.
  • the molar volume ratio of the compound of formula II in the step (a) of the preparation method of the intermediate compound 6 to the solvent is 1 mmol: (1-5 mL); preferably, the formula II in the step (a) The molar volume ratio of the compound to the solvent is 1mmol:(1-3mL); further preferably, the molar volume ratio of the compound of formula II in step (a) to the solvent is 1mmol:(1-2mL).
  • the molar volume ratio of the compound of formula II and the solvent in step (a) is 1mmol: 1mL, 1mmol: 1.1mL, 1mmol: 1.2mL, 1mmol: 1.3mL, 1mmol: 1.4mL, 1mmol: 1.5mL, 1mmol: 1.6 mL, 1 mmol: 1.7 mL, 1 mmol: 1.8 mL, 1 mmol: 1.9 mL, or 1 mmol: 2 mL.
  • the molar volume ratio of the compound of formula II to the solvent in step (a) of the preparation method of the intermediate compound 6 is 1 mmol: 1.7 mL.
  • the reaction temperature of step (a) of the preparation method of intermediate compound 6 is 10°C-50°C; preferably, the reaction temperature of step (a) is 10°C-30°C; Further preferably, the reaction temperature in step (a) is 20°C to 30°C. In a specific embodiment of the present application, the reaction temperature of the step (a) of the preparation method of the intermediate compound 6 is 25°C to 30°C.
  • the reaction time of step (a) of the preparation method of the intermediate compound 6 is 1 to 10 hours; preferably, the reaction time of step (a) is 2 to 6 hours; more preferably Preferably, the reaction time of step (a) is 3 to 5 hours. In a specific embodiment of the present application, the reaction time of the step (a) of the preparation method of the intermediate compound 6 is 5 hours.
  • the preparation method of the intermediate compound 6 further comprises: (b) further adding a solvent to the reaction system in step (a), stirring, and filtering to obtain the purified intermediate compound 6.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 is 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 one or more mixed solvents in DMSO.
  • the solvent described in step (b) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether, and acetonitrile. Further preferably, the solvent described in step (b) is selected from one of methanol, ethanol, acetone, and methyl tert-butyl ether. In a specific embodiment of the present application, the solvent in the step (b) of the preparation method of the intermediate compound 6 is selected from ethanol. In another specific embodiment of the present application, the solvent in the step (b) of the preparation method of the intermediate compound 6 is selected from acetone.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether , the mixed solvent of any two solvents in acetonitrile;
  • the solvent described in step (b) is selected from the mixing solvent of methanol and methyl tert-butyl ether, the mixed solvent of acetone and ethanol, Virahol and acetonitrile solvent, a mixed solvent of n-butanol and acetonitrile.
  • 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.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 is selected from a mixed solvent of acetone and ethanol.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl tert-butyl ether .
  • a mixed solvent of any two solvents in acetonitrile; the volume ratio of the two solvents is 1:(0.5-10), and the two solvents corresponding to the volume ratio are interchangeable.
  • the volume ratio of ethanol and acetone may be 1:(0.5 ⁇ 10), or the volume ratio of acetone and ethanol may be 1:(0.5 ⁇ 10).
  • 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); further preferably, the two The volume ratio of the solvent 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.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 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); Preferably, the volume ratio of the ethanol and acetone is 1:(0.5 ⁇ 6); More preferably, the volume ratio of the ethanol and acetone is 1:(0.5 ⁇ 4); Even more preferably Ground, the volume ratio of described 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.
  • the solvent described in the step (b) of the preparation method of the intermediate compound 6 is selected from a mixed solvent of ethanol and acetone; the volume ratio of the volume of the volume of the ethanol and acetone is 1: (0.5
  • the solvent described in the 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 methanol and methyl tert-butyl ether is 1:(0.5 ⁇ 10); preferably, the volume ratio of methanol and methyl tert-butyl ether is 1:(0.5 ⁇ 6); further preferably, the The volume ratio of methanol and methyl tert-butyl ether is 1:(0.5 ⁇ 4); more preferably, the volume ratio of 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.
  • the solvent described in the 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 methanol and methyl The volume ratio of tert-butyl ether is 1:1.
  • the volume-to-mass ratio of the solvent described in step (b) of the preparation method of the intermediate compound 6 to the compound of formula II in step (a) is (2-20 mL): 1 g; preferably Preferably, the volume mass ratio of the solvent described in step (b) to the compound of formula II in step (a) is (5-15mL): 1g; further preferably, the solvent described in step (b) and the compound of formula II in step (a)
  • the volume mass ratio of the compound is (10-15mL): 1g; more preferably, the volume mass ratio of the solvent described in step (b) to the compound of formula II in step (a) is 10mL: 1g, 10.5mL: 1g, 11mL : 1g, 11.5mL: 1g, 12mL: 1g, 12.5mL: 1g, 13mL: 1g, 13.5mL: 1g, 14mL: 1g, 14.5mL: 1g, 15mL: 1g.
  • the volume mass ratio of the compound is (10
  • the stirring temperature in the step (b) of the preparation method of the intermediate compound 6 is 10° C. to 50° C.; preferably, the stirring temperature in the step (b) is 10° C. to 30° C. °C; further preferably, the stirring temperature in step (b) is 20 °C to 30 °C. In a specific embodiment of the present application, the stirring temperature in the step (b) of the preparation method of the intermediate compound 6 is 25°C to 30°C.
  • the stirring time in the step (b) of the preparation method of the intermediate compound 6 is 2 to 20 hours; preferably, the stirring time in the step (b) is 5 to 15 hours; More preferably, the stirring time in step (b) is 10-15 hours. In a specific embodiment of the present application, the stirring time in the step (b) of the preparation method of the intermediate compound 6 is 12 hours.
  • the preparation method of the intermediate compound 6 further includes a refining step (c) of the intermediate compound 6: the intermediate compound 6 obtained by filtering the step (b) is further heated and stirred with a solvent, and then Cool down and stir, and filter to obtain the refined intermediate compound 6.
  • the solvent described in the refining step (c) of the intermediate compound 6 is selected from water, dichloromethane, methanol, ethanol, isopropyl Alcohol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, One or more mixed solvents in toluene, xylene, DMF, DMAC or DMSO;
  • the solvent described in the refining step (c) is selected from methanol, ethanol, Virahol, n-butanol, acetone, One or more mixed solvents in methyl tert-butyl ether and acetonitrile;
  • the solvent described in the refining step (c) is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl tertiary A mixed solvent of any two solvents in butyl ether and acetonitrile; preferably, the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of acetone and ethanol, iso A mixed solvent of propanol and acetonitrile, a mixed solvent of n-butanol and acetonitrile; further preferably, the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of acetone and ethanol.
  • the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of
  • the solvent described in the refining step (c) is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl tertiary A mixed solvent of any two solvents in butyl ether and acetonitrile; the volume ratio of the two solvents is 1:(0.5-10), and the two solvents corresponding to the volume ratio are interchangeable.
  • 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).
  • 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); further preferably, the two The volume ratio of the solvent 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.
  • the solvent described in the refining step (c) is selected from a mixed solvent of ethanol and acetone; the volume ratio of the ethanol and acetone is 1 :(0.5 ⁇ 10); Preferably, the volume ratio of the ethanol and acetone is 1:(0.5 ⁇ 6); More preferably, the volume ratio of the ethanol and acetone is 1:(0.5 ⁇ 4); Further Preferably, the volume ratio of the 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, 1:2.7 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.
  • the solvent described in the refining step (c) is selected from a mixed solvent of ethanol and acetone; the volume ratio of ethanol and acetone 1:1.
  • the solvent described in the refining step (c) is selected from a mixed solvent of ethanol and acetone; the volume of the ethanol and acetone The ratio is 1:2.
  • the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether; the methanol and methyl
  • the volume ratio of methyl tert-butyl ether is 1:(0.5 ⁇ 10); preferably, the volume ratio of said methanol and methyl tert-butyl ether is 1:(0.5 ⁇ 6); further preferably, said methanol and The volume ratio of methyl tert-butyl ether is 1:(0.5 ⁇ 4); more 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.
  • the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether; the methanol The volume ratio to methyl tert-butyl ether is 1:1.
  • the solvent described in the refining step (c) is selected from a mixed solvent of methanol and methyl tert-butyl ether; The volume ratio of methanol and methyl tert-butyl ether is 1:1.5.
  • the volume mass ratio of the solvent described in the refining step (c) to the compound of formula II in the step (a) is (2 ⁇ 20mL): 1g; preferably, the volume-to-mass ratio of the solvent described in the refining step (c) to the compound of formula II in step (a) is (2-10mL): 1g; further preferably, the solvent described in the refining step (c)
  • the volume mass ratio to the compound of formula II in step (a) is (2 ⁇ 5mL): 1g; more preferably, the volume mass ratio of the solvent described in the refining step (c) to the compound of formula II in step (a) is 2mL : 1g, 2.5mL: 1g, 3mL: 1g, 3.5mL: 1g, 4mL: 1g, 4.5mL: 1g, 5mL: 1g.
  • the volume-mass ratio of the solvent described in the refining step (c) to the compound of formula II in step (a) is (2-10mL): 1
  • the heating and stirring temperature in the refining step (c) is 30°C to 80°C; preferably, the heating in step (c) The stirring temperature is 30°C-50°C; further preferably, the heating and stirring temperature in the refining step (c) is 40°C-50°C. In a specific embodiment of the present application, regarding the preparation method of the intermediate compound 6, the heating and stirring temperature in the refining step (c) is 45°C to 50°C.
  • the cooling and stirring temperature in the refining step (c) is 0°C to 30°C; preferably, the cooling in step (c) The stirring temperature is 0°C-20°C; further preferably, the cooling stirring temperature in the refining step (c) is 5°C-20°C. In a specific embodiment of the present application, regarding the preparation method of the intermediate compound 6, the cooling and stirring temperature in the refining step (c) is 5°C to 15°C.
  • the heating and stirring time described in the refining step (c) is 0.5 to 5 hours; preferably, the refining step (c) described The heating and stirring time is 0.5 to 3 hours; further preferably, the heating and stirring time in the refining step (c) is 1 to 3 hours. In a specific embodiment of the present application, regarding the preparation method of the intermediate compound 6, the heating and stirring time in the refining step (c) is 2 hours.
  • the cooling and stirring time described in the refining step (c) is 2 to 20 hours; preferably, the refining step (c) described The cooling and stirring time is 2 to 15 hours; further preferably, the cooling and stirring time in the refining step (c) is 5 to 15 hours. In a specific embodiment of the present application, regarding the preparation method of the intermediate compound 6, the cooling and stirring time in the refining step (c) is 6 hours.
  • the present application provides a preparation method of the compound of formula II, the preparation method comprising: reacting the compound of formula IV and the compound of formula III in the presence of a reducing agent and a solvent to obtain the compound of formula II.
  • the reducing agent in the preparation method of the compound of formula II is selected from formic acid, formic acid/palladium carbon, ammonium formate/palladium carbon, hydrazine hydrate/palladium carbon, Raney nickel/hydrazine hydrate, three Sodium acetoxyborohydride, 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 triacetoxy Sodium borohydride, 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 specific embodiment of the present application, the reducing agent in the preparation method of the compound of formula II is selected from sodium triacetoxyborohydride
  • the reducing agent in the preparation method of the compound of formula II can optionally be used in the presence of a catalyst, and the catalyst is 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, guanidine hydrochloride, pyridine p-toluenesulfonate, titanium tetrachloride, tetraisopropyl titanate 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.
  • the reducing agent in the preparation method of the compound of formula II is used in the presence of a catalyst, and the catalyst is selected from
  • the solvent described in the preparation method of the compound of formula II is selected from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane , acetone, ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO or multiple mixed solvents; preferably, the solvent is selected from dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptyl
  • the solvent is selected from dichloromethane, methanol
  • 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 The ratio 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.
  • 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.
  • 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 specific 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.
  • 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 and 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 specific 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.
  • the molar volume ratio of the compound of formula III to the solvent in the preparation method of the compound of formula II is 1mmol:(1 ⁇ 10mL); preferably, the molar volume ratio of the compound of formula III to the solvent is 1mmol: (1 ⁇ 5mL); Further preferably, the molar volume ratio of formula III compound and solvent is 1mmol:(2 ⁇ 4mL); Even more preferably, the molar volume ratio of formula III compound and solvent is 1mmol:2mL, 1mmol : 2.5mL, 1mmol: 3mL, 1mmol: 3.1mL, 1mmol: 3.2mL, 1mmol: 3.3mL, 1mmol: 3.4mL, 1mmol: 3.5mL, 1mmol: 3.6mL, 1mmol: 3.7mL, 1mmol: 3.8mL, 1mmol: 3.9mL, 1mmol: 4mL.
  • the molar volume ratio of the compound of the solvent of the solvent is 1mmol:(1 ⁇ 10mL
  • the reaction temperature in the preparation method of the compound of formula II is 10°C to 50°C; preferably, the reaction temperature is 10°C to 30°C; more preferably, the reaction temperature It is 20°C to 35°C. In a specific embodiment of the present application, the reaction temperature in the preparation method of the compound of formula II is 25°C-35°C.
  • the reaction time in the preparation method of the compound of formula II is 2 to 24 hours; preferably, the reaction time is 5 to 20 hours; more preferably, the reaction time is 5 ⁇ 15 hours. In a specific embodiment of the present application, the reaction time in the preparation method of the compound of formula II is 10 hours.
  • the present application provides a preparation method of a compound of formula (I), the preparation method comprising: (1) reacting the compound of formula II in the presence of hydrochloric acid and a solvent to obtain intermediate compound 6; (2) intermediate Compound 6 reacts with compound 7 in the presence of a solvent and a base to obtain compound 8; (3) reacts compound 8 and compound 9 in the presence of a solvent and an acid to obtain a compound of formula (I).
  • step (1) in the preparation method of the compound of formula (I), the conditions of step (1) are the same as step (a) of the above-mentioned preparation method of intermediate compound 6.
  • the preparation method of the compound of formula (I) further includes: (1') further adding a solvent to the reaction system of step (1), stirring, and filtering to obtain purified intermediate compound 6.
  • the condition of the step (1') is as the step (b) of the preparation method of the above-mentioned intermediate compound 6.
  • the preparation method of the compound of formula (I) further includes the refining step (1") of the intermediate compound 6: the intermediate compound 6 obtained by filtering the step (1') is further heated with a solvent Stir, then lower the temperature and stir, filter to obtain refined intermediate compound 6.
  • the conditions of the refining step (1") of the intermediate compound 6 are as in the step (c) of the above-mentioned intermediate compound 6 preparation method.
  • the solvent described in step (2) of the preparation method of the compound of formula (I) is selected from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1 , one or more mixed solvents in 4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent described in step (2) is selected from One or more mixed solvents in methanol, ethanol, Virahol, n-butanol, acetone, acetonitrile; further preferably, the solvent described in step (2) is selected from one of methanol, ethanol, acetonitrile ; In a specific embodiment of the present application, the solvent described in the step (2) of the preparation method of the compound of formula (I) is selected from acetonitrile.
  • the base described in the step (2) of the preparation method of the compound of formula (I) is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, triethyl One or more in amine, pyridine, triethanolamine, sodium hydroxide, potassium hydroxide or calcium hydroxide;
  • the base described in step (2) is selected from sodium carbonate, potassium carbonate, calcium carbonate, hydrogen One or more in sodium oxide, potassium hydroxide or calcium hydroxide;
  • the alkali described in step (2) is selected from a kind of in sodium carbonate, potassium carbonate or calcium carbonate;
  • the base described in the step (2) of the preparation method of the compound of formula (I) is selected from sodium carbonate.
  • the molar ratio of the intermediate compound 6 to the compound 7 is 1:(1 ⁇ 3); preferably, the intermediate The molar ratio of compound 6 to compound 7 is 1:(1 ⁇ 1.5); more 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.
  • the molar ratio of the intermediate compound 6 to the compound 7 is 1:1.05.
  • the molar ratio of the intermediate compound 6 to the base is 1:(1-8); preferably, the intermediate compound The molar ratio of 6 to the base is 1:(1-5); more preferably, the molar ratio of the intermediate compound 6 to the base is 1:1, 1:2, 1:3, 1:4, 1:5.
  • the molar ratio of the intermediate compound 6 to the base is 1:3.
  • the reaction temperature of step (2) in the preparation method of the compound of formula (I) is 50°C-120°C; preferably, the reaction temperature is 80°C-120°C; more preferably, The reaction temperature is 80°C to 100°C. In a specific embodiment of the present application, the reaction temperature of step (2) in the preparation method of the compound of formula (I) is 80°C-90°C.
  • the reaction time of step (2) in the preparation method of the compound of formula (I) is 2 to 24 hours; preferably, the reaction time is 10 to 24 hours; more preferably, the reaction time 10 to 20 hours. In a specific embodiment of the present application, the reaction time of step (2) in the preparation method of the compound of formula (I) is 16 hours.
  • step (2) in the preparation method of the compound of formula (I) further includes: (2') adding a solvent to the compound 8 obtained in step (2) and stirring, filtering, and beating the filter cake The solvent was stirred and washed, filtered, and the filter cake was dried to obtain refined compound 8.
  • the solvent described in step (2') in the preparation method of the compound of formula (I) is selected from water, methanol, ethanol, isopropanol, n-butanol, 1,4- A mixed solvent of one or more of dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile; preferably, the solvent in step (2') is selected from water.
  • the beating solvent described in step (2') in the preparation method of the compound of formula (I) is selected from methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane One or more mixed solvents;
  • the beating solvent described in step (2') is selected from methyl tert-butyl ether.
  • the solvent described in step (3) in the preparation method of the compound of formula (I) is selected from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1 , one or more mixed solvents in 4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent described in step (3) is selected from One or more mixed solvents in methanol, ethanol, Virahol, n-butanol, 1,4-dioxane, acetonitrile; further preferably, the solvent described in step (3) is selected from methanol, One in ethanol, 1,4-dioxane, acetonitrile; In a specific embodiment of the present application, the solvent described in step (3) in the preparation method of the compound of formula (I) is selected from 1 ,4-dioxane
  • the acid described in step (3) in the preparation method of the compound of formula (I) is selected from p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, One or more of hydrofluoric acid, formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hydrochloric acid, phosphoric acid or sulfuric acid;
  • the acid described in step (3) is selected from p-toluenesulfonic acid, trifluoro One or more of acetic acid, trifluoromethanesulfonic acid or methanesulfonic acid; further preferably, the acid described in step (3) is selected from one of p-toluenesulfonic acid and trifluoroacetic acid; in the application In a specific embodiment, the acid described in step (3) in the preparation method of the compound of formula (I) is selected from p-
  • the molar ratio of compound 8 and compound 9 in step (3) in the preparation method of the compound of formula (I) is 1:(1 ⁇ 3); preferably, compound 8 and compound 9
  • the molar ratio of compound 8 is 1:(1 ⁇ 1.5); more preferably, the molar ratio of compound 8 and 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.
  • the molar ratio of compound 8 to compound 9 in step (3) in the preparation method of the compound of formula (I) is 1:1.05.
  • the molar ratio of compound 8 and acid in step (3) in the preparation method of the compound of formula (I) is 1:(1 ⁇ 8); preferably, the molar ratio of compound 8 and acid The ratio is 1:(1-5); more preferably, the molar ratio of compound 8 to acid is 1:1, 1:2, 1:3, 1:4, 1:5.
  • the molar ratio of the compound 8 in step (3) to the acid in the preparation method of the compound of formula (I) is 1:3.
  • the reaction temperature of step (3) in the preparation method of the compound of formula (I) is 50°C to 120°C; preferably, the reaction temperature is 80°C to 120°C; more preferably, The reaction temperature is 90°C to 110°C. In a specific embodiment of the present application, the reaction temperature of step (3) in the preparation method of the compound of formula (I) is 95°C-105°C.
  • the reaction time of step (3) in the preparation method of the compound of formula (I) is 2 to 24 hours; preferably, the reaction time is 10 to 24 hours; more preferably, the reaction time 10 to 20 hours. In a specific embodiment of the present application, the reaction time of step (3) in the preparation method of the compound of formula (I) is 16 hours.
  • the present application provides a preparation method of a compound of formula (I), the preparation method comprising: (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) the compound of formula II is reacted in the presence of hydrochloric acid and a solvent to obtain an intermediate compound 6; (iii) the intermediate compound 6 is reacted with a compound 7 in the presence of a solvent and a base to obtain a compound 8; (iv) a compound 8 and a compound 9 is reacted in the presence of solvent and acid to give the compound of formula (I).
  • step (i), step (ii), step (iii) and step (iv) are respectively as the preparation method of the compound of formula II above and the preparation of intermediate compound 6
  • the method step (a), the preparation method step (2) of the compound of formula (I) and the preparation method step (3) of the compound of formula (I) are described.
  • the preparation method of the compound of formula (I) further comprises: (ii') further adding a solvent to the reaction system of step (ii), stirring, and filtering to obtain purified intermediate compound 6.
  • the condition of the step (ii') is as the step (b) of the preparation method of the above-mentioned intermediate compound 6.
  • the preparation method of the compound of formula (I) further includes the refining step (ii") of the intermediate compound 6: the intermediate compound 6 obtained by filtering the step (ii') is further heated with a solvent Stir, then lower the temperature and stir, filter to obtain refined intermediate compound 6.
  • the conditions of the refining step (ii") of the intermediate compound 6 are as described in step (c) of the preparation method of the intermediate compound 6.
  • the present application also provides a preparation method of the compound of formula IV.
  • the preparation method of the compound of formula IV comprises: reacting the compound of formula VI and the compound of formula V in the presence of a solvent to obtain the compound of formula IV.
  • the solvent in the preparation method of the compound of formula IV is selected from water, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2 - one or more mixed solvents in methyltetrahydrofuran, acetonitrile, DMF, DMAC or DMSO; preferably, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile a mixed solvent; further preferably, the solvent is selected from one or more mixed solvents in water, methanol, ethanol or isopropanol. In a specific embodiment of the present application, in the preparation method of the compound of formula IV, the solvent is selected from water.
  • the molar ratio of the compound of formula VI to the compound of formula V is 1:(1 ⁇ 3); preferably, the molar ratio of the compound of formula VI to the compound of formula V The ratio 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.
  • the molar ratio of the compound of formula VI to the compound of formula V is 1:1.1.
  • the molar volume ratio of the compound of formula VI to the solvent is (1 ⁇ 5mmol): 1mL; preferably, the molar volume ratio of the compound of formula VI to the solvent is (2 ⁇ 4mmol): 1mL; further preferably, the molar volume ratio of the compound of formula VI to the solvent is 2mmol: 1mL, 2.5mmol: 1mL, 3mmol: 1mL, 3.5mmol: 1mL, 4mmol: 1mL.
  • the molar volume ratio of the compound of formula VI to the solvent is 3 mmol: 1 mL.
  • the reaction temperature in the preparation method of the compound of formula IV is 10°C-50°C; preferably, the reaction temperature is 10°C-40°C; more preferably, the reaction temperature is 20°C-40°C °C. In a specific embodiment of the present application, the reaction temperature in the preparation method of the compound of formula IV is 20°C-30°C.
  • 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; more preferably, the reaction time is 10-20 hours. In a specific embodiment of the present application, the reaction time in the preparation method of the compound of formula IV is 12 hours.
  • the application also provides a preparation method of intermediate compound 6 for the preparation of compounds of formula (I).
  • the preparation method of 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.
  • step (a) the conditions of step (a) are as above.
  • the present application also provides a method for preparing the compound of formula (I), the method comprising: preparing intermediate compound 6 from the compound of formula II according to the above-mentioned method of the present application, and further preparing the compound of formula (I).
  • the method for preparing the compound of formula (I) further comprises the following steps: the step of preparing the compound of formula II from the compound of formula IV and the compound of formula III according to the above-mentioned method of the present application, and/or the compound of formula VI according to the above-mentioned method of the present application and formula V compound to prepare the step of formula IV compound.
  • the compound of formula II can be reacted under the conditions of hydrochloric acid and a specific solvent.
  • the high-purity trans-isomer intermediate compound 6 is directly prepared, and the obtained product is convenient for subsequent further purification. It has the advantages of mild reaction conditions, short reaction steps, short reaction time, simple post-treatment operation, and high isomer purity. It is very suitable for Industrial production.
  • the "DMAC” mentioned in this application is N,N-dimethylacetamide.
  • DMSO dimethyl sulfoxide
  • MTBE as used herein is methyl tert-butyl ether.
  • acids and bases described herein include anhydrous and hydrated forms.
  • hydrochloric acid includes hydrogen chloride gas and hydrogen chloride solutions, including aqueous solutions and organic solvent solutions.
  • concentrated hydrochloric acid refers to an aqueous solution of hydrogen chloride with a mass fraction of hydrogen chloride exceeding 20%.
  • concentration of concentrated hydrochloric acid may be 36%-38%, that is, an aqueous hydrogen chloride solution with a mass fraction of hydrogen chloride of 36%-38%.
  • the compound of formula IV described in this application can also be prepared from the compound of formula VI and compound of formula V in the presence of a solvent by the above-mentioned preparation method of the compound of formula IV.
  • Embodiment 1 the preparation of formula IV compound
  • Embodiment 2 the preparation of formula II compound
  • the aqueous phases were combined, extracted once with dichloromethane (300 mL), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 30 ⁇ 5°C.
  • Embodiment 3-1 Preparation of intermediate compound 6
  • Embodiment 3-2 Preparation of intermediate compound 6
  • Embodiment 3-3 the preparation of intermediate compound 6
  • Embodiment 4 the preparation of formula (I) compound
  • Embodiment 5 the preparation of formula (I) compound hydrochloride

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Abstract

提供一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法，具体涉及式（Ⅰ）化合物及其中间体化合物6的制备方法。获得反式异构体的方法具有反应条件温和、反应步骤短、反应时间短、后处理操作简单、异构体纯度高等优点，非常适合工业化生产。

Description

一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法
相关申请的引用
本申请要求于2021年12月10日向中华人民共和国国家知识产权局提交的第202111508482.8号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请属于医药化工领域，涉及一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法，具体涉及式(I)化合物：4-((1R,4R)-4-((3-甲基-6-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)异噻唑并[5,4-d]嘧啶-4-基)氨基)环己基)哌嗪-1-羧酸甲酯及其中间体化合物6：4-((1R,4R)-4-氨基环己基)哌嗪-1-羧酸甲酯的制备方法。
背景技术
白细胞介素1受体激酶4(IRAK4)是一种丝氨酸/苏氨酸特异性蛋白激酶，属于类酪氨酸激酶(TLK)家族成员，是白介素-1、白介素-18、白介素-33受体和Toll样受体参与的先天性免疫应答中的关键节点。细胞外信号分子与白介素受体或Toll样受体结合后，募集形成MyD88:IRAK4:IRAK1/2多蛋白复合体，导致IRAK1/2磷酸化，介导一系列下游信号传导，从而激活p38、JNK和NF-kB信号通路，最终导致前炎症细胞因子的表达。临床病理学研究表明，具有IRAK4突变的个体对慢性肺病、炎症性肠病有防护作用。IRAK4缺陷本身无致死性，个体能够存活至成年，且随年龄增长受感染风险降低。因此，IRAK4成为了一类重要治疗靶点，吸引了广泛的研发兴趣。
WO2021147968公开了一种式(I)化合物，并公开了式(I)化合物的制备方法，所述制备方法如下述路线所示：
Figure PCTCN2022138020-appb-000001
其中，中间体化合物6是式(I)化合物制备的关键中间体，但中间体化合物6的制备方法中引入了昂贵的反式异构体化合物2作为起始原料，同时引入了金属钯催化剂脱苄基保护，且该方法制备路线较长，收率较低，不适用于工业化生产。
因此，需要提供一条更经济、方便，收率更高，更适合工业化生产的式(I)化合物的制备方法。
发明内容
一方面，本申请提供一种中间体化合物6的制备方法，所述制备方法包括：(a)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6。
Figure PCTCN2022138020-appb-000002
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自氯化氢气体、或氯化氢的溶液，例如氯化氢的水溶液、氯化氢的有机溶剂溶液、或二者的混合溶液。例如，步骤(a)中所述的盐酸为氯化氢的溶液，包括水溶液和有机溶剂溶液或其混合溶液。在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自盐酸/水溶液、盐酸/甲醇溶液、盐酸/乙酸乙酯溶液、盐酸/丙酮溶液、盐酸/乙醇溶液、或盐酸/二氧六环溶液。在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自盐酸/水溶液、氯化氢/甲醇和水的混合溶液、氯化氢/乙酸乙酯和水的混合溶液、氯化氢/丙酮和水的混合溶液、氯化氢/乙醇和水的混合溶液、氯化氢/乙酸乙酯溶液、氯化氢/甲醇溶液、氯化氢/乙醇溶液或氯化氢/二氧六环溶液。本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自浓盐酸、浓盐酸/甲醇溶液、浓盐酸/乙酸乙酯溶液、浓盐酸/丙酮溶液、浓盐酸/乙醇溶液、氯化氢/乙酸乙酯溶液、氯化氢/甲醇溶液、氯化氢/乙醇溶液或氯化氢/二氧六环溶液。在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自浓盐酸、盐酸/甲醇溶液、盐酸/乙酸乙酯溶液、盐酸/丙酮溶液、盐酸/乙醇溶液、氯化氢/乙酸乙酯溶液、氯化氢/甲醇溶液、氯化氢/乙醇溶液或氯化氢/二氧六环溶液。优选地，步骤(a)中所述的盐酸选自30％-60％浓盐酸；或者，步骤(a)中所述的盐酸选自1-10mol/L的氯化氢溶液，包括氯化氢的有机溶剂溶液，或氯化氢的有机溶剂和水的混合溶液。更优选地，步骤(a)中所述的盐酸选自30％-60％浓盐酸，或选自1-10mol/L的盐酸/甲醇溶液、盐酸/乙酸乙酯溶液、盐酸/丙酮溶液、盐酸/乙醇溶液、氯化氢/乙酸乙酯溶液、氯化氢/甲醇溶液、氯化氢/乙醇溶液或氯化氢/二氧六环溶液。进一步优选地，步骤(a)中所述的盐酸选自30％-40％浓盐酸。进一步优选地，步骤(a)中所述的盐酸选自36％-38％浓盐酸。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的盐酸选自37％浓盐酸。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的溶剂选自乙醇、丙酮、甲基叔丁基醚中的一种。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)中所述的溶剂选自丙酮。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中的式II化合物与盐酸的摩尔比为1:(1～10)；优选地，步骤(a)中式II化合物与盐酸的摩尔比为1:(1～5)；进一步优选地，步骤(a)中式II化合物与盐酸的摩尔比为1:(3～5)。更进一步优选地，步骤(a)中式II化合物与盐酸的摩尔比为1:3、1:3.5、1:4、1:4.5、1:5。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)中式II化合物与盐酸的摩尔比为1:5。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中的式II化合物与氯化氢的摩尔比为1:(1～10)；优选地，步骤(a)中式II化合物与氯化氢的摩尔比为1:(1～5)；进一步优选地，步骤(a)中式II化合物与氯化氢的摩尔比为1:(3～5)。更进一步优选地，步骤(a)中式II化合物与氯化氢的摩尔比为1:3、1:3.5、1:4、1:4.5、1:5。在本申请具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)中式II化合物与氯化氢的摩尔比为1:5。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)中式II化合物与溶剂的摩尔体积比为1mmol:(1～5mL)；优选地，步骤(a)中式II化合物与溶剂的摩尔体积比为1mmol:(1～3mL)；进一步优选地，步骤(a)中式II化合物与溶剂的摩尔体积比为1mmol:(1～2mL)。更进一步优选地，步骤(a)中式II化合物与溶剂的摩尔体积比为1mmol:1mL、1mmol:1.1mL、1mmol:1.2mL、1mmol:1.3mL、1mmol:1.4mL、1mmol:1.5mL、1mmol:1.6mL、1mmol:1.7mL、1mmol:1.8mL、1mmol:1.9mL、或1mmol:2mL。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)中式II化合物与溶剂的摩尔体积比为1mmol:1.7mL。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)的反应温度为10℃～50℃；优选地，步骤(a)的反应温度为10℃～30℃；进一步优选地，步骤(a)的反应温度为20℃～30℃。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)的反应温度为25℃～30℃。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(a)的反应时间为1～10小时；优选地，步骤(a)的反应时间为2～6小时；进一步优选地，步骤(a)的反应时间为3～5小时。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(a)的反应时间为5小时。
在本申请的一些实施方案中，所述中间体化合物6的制备方法进一步包括：(b)向步骤(a)的反应体系中进一步加入溶剂搅拌，过滤，得到纯化的中间体化合物6。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、乙醚、甲基叔丁基醚、乙酸乙酯、乙酸丁酯、四氢呋喃、2-甲基四氢呋喃、正庚烷、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或多种混合的溶剂。优选地，步骤(b)所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的一种或多种混合的溶剂。进一步优选地，步骤(b)所述的溶剂选自甲醇、乙醇、丙酮、甲基叔丁基醚中的一种。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自乙醇。在本申请另一具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自丙酮。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的任意两种溶剂的混合溶剂；优选地，步骤(b)所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂、丙酮和乙醇的混合溶剂、异丙醇和乙腈的混合溶剂、正丁醇和乙腈的混合溶剂。进一步优选地，步骤(b)所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂、丙酮和乙醇的混合溶剂。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自丙酮和乙醇的混合溶剂。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的任意两种溶剂的混合溶剂；所述两种溶剂的体积比为1:(0.5～10)，所述体积比对应的两种溶剂可互换。例如，在乙醇和丙酮的混合溶剂的情况中，乙醇和丙酮的体积比可为1:(0.5～10)，或丙酮和乙醇的体积比可为1:(0.5～10)。优选地，所述两种溶剂的体积比为1:(0.5～6)；进一步优选地，所述两种溶剂的体积比为1:(0.5～4)；更进一步优选地，所述两种溶剂的体积比为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。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述乙醇和丙酮混合溶剂的体积比为1:(0.5～10)；优选地，所述乙醇和丙酮的体积比为1:(0.5～6)；进一步优选地，所述乙醇和丙酮的体积比为1:(0.5～4)；更进一步优选地，所述乙醇和丙酮的体积比为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。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述乙醇和丙酮的体积比为1:2.8。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；在所述混合溶剂中所述甲醇和甲基叔丁基醚的体积比为1:(0.5～10)；优选地，所述甲醇和甲基叔丁基醚的体积比为1:(0.5～6)；进一步优选地，所述甲醇和甲基叔丁基醚的体积比为1:(0.5～4)；更进一步优选地，所述甲醇和甲基叔丁基醚的体积比为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。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂，所述甲醇和甲基叔丁基醚的体积比为1:1。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中所述的溶剂与步骤(a)中式II化合物的体积质量比为(2～20mL):1g；优选地，步骤(b)所述的溶剂与步骤(a)中式II化合物的体积质量比为(5～15mL):1g；进一步优选地，步骤(b)所述的溶剂与步骤(a)中式II化合物的体积质量比为(10～15mL):1g；更进一步优选地，步骤(b)所述的溶剂与步骤(a)中式II化合物的体积质量比为 10mL:1g、10.5mL:1g、11mL:1g、11.5mL:1g、12mL:1g、12.5mL:1g、13mL:1g、13.5mL:1g、14mL:1g、14.5mL:1g、15mL:1g。在本申请的一个具体的实施方案中，在所述中间体化合物6的制备方法中，步骤(b)所述的溶剂与步骤(a)中式II化合物的体积质量比为13.5mL:1g。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中的搅拌温度为10℃～50℃；优选地，步骤(b)中的搅拌温度为10℃～30℃；进一步优选地，步骤(b)中的搅拌温度为20℃～30℃。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中的搅拌温度为25℃～30℃。
在本申请的一些实施方案中，所述中间体化合物6的制备方法的步骤(b)中的搅拌时间为2～20小时；优选地，步骤(b)中的搅拌时间为5～15小时；进一步优选低地，步骤(b)中的搅拌时间为10～15小时。在本申请的一个具体的实施方案中，所述中间体化合物6的制备方法的步骤(b)中的搅拌时间为12小时。
在本申请的一些实施方案中，所述中间体化合物6的制备方法进一步包括中间体化合物6的精制步骤(c)：将步骤(b)过滤得到的中间体化合物6进一步与溶剂加热搅拌，再降温搅拌，过滤，得到精制的中间体化合物6。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中中间体化合物6的精制步骤(c)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、乙醚、甲基叔丁基醚、乙酸乙酯、乙酸丁酯、四氢呋喃、2-甲基四氢呋喃、正庚烷、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或多种混合的溶剂；优选地，精制步骤(c)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的一种或多种混合的溶剂；进一步优选地，精制步骤(c)中所述的溶剂选自甲醇、乙醇、丙酮、甲基叔丁基醚中的一种。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自乙醇。在本申请的另一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自丙酮。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的任意两种溶剂的混合溶剂；优选地，精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂、丙酮和乙醇的混合溶剂、异丙醇和乙腈的混合溶剂、正丁醇和乙腈的混合溶剂；进一步优选地，精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂、丙酮和乙醇的混合溶剂。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自丙酮和乙醇的混合溶剂。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的任意两种溶剂的混合溶剂；所述两种溶剂的体积比为1:(0.5～10)，所述体积比对应的两种溶剂可互换。例如，在乙醇和丙酮的混合溶剂的情况中，乙醇和丙酮的体积比为1:(0.5～10)，或丙酮和乙醇的体积比为1:(0.5～10)。优选地，所述两种溶剂的体积比为1:(0.5～6)；进一步优选地，所述两种溶剂的体积比为1:(0.5～4)；更进一步优选地，所述两种溶剂的体积比为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。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述乙醇和丙酮的体积比为1:(0.5～10)；优选地，所述乙醇和丙酮的体积比为1:(0.5～6)；进一步优选地，所述乙醇和丙酮的体积比为1:(0.5～4)；更进一步优选地，所述乙醇和丙酮的体积比为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。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述乙醇和丙酮的体积比为1:1。在本申请的另一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述乙醇和丙酮的体积比为1:2。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；所述甲醇和甲基叔丁基醚的体积比为1:(0.5～10)；优选地，所述甲醇和甲基叔丁基醚的体积比为1:(0.5～6)；进一步优选地，所述甲醇和甲基叔丁基醚的体积比为1:(0.5～4)；更进一步优选地，所述甲醇和甲基叔丁基醚的体积比为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。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；所述甲醇和甲基叔丁基醚的体积比为1:1。在本申请的另一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；所述甲醇和甲基叔丁基醚的体积比为1:1.5。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂与步骤(a)中式II化合物的体积质量比为(2～20mL):1g；优选地，精制步骤(c)中所述的溶剂与步骤(a)中式II化合物的体积质量比为(2～10mL):1g；进一步优选地，精制步骤(c)中所述的溶剂与步骤(a)中式II化合物的体积质量比为(2～5mL):1g；更进一步优选地，精制步骤(c)中所述的溶剂与步骤(a)中式II化合物的体积质量比为2mL:1g、2.5mL:1g、3mL:1g、3.5mL:1g、4mL:1g、4.5mL:1g、5mL:1g。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂与步骤(a)中式II化合物的体积质量比为4mL:1g。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的加热搅拌温度为30℃～80℃；优选地，步骤(c)中的加热搅拌温度为30℃～50℃；进一步优选地，精制步骤(c)中所述的加热搅拌温度为40℃～50℃。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的加热搅拌温度为45℃～50℃。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的降温搅拌温度为0℃～30℃；优选地，步骤(c)中的降温搅拌温度为0℃～20℃；进一步优选地，精制步骤(c)中所述的降温搅拌温度为5℃～20℃。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的降温搅拌温度为5℃～15℃。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的加热搅拌时间为0.5～5小时；优选地，精制步骤(c)中所述的加热搅拌时间为0.5～3小时；进一步优选地，精制步骤(c)中所述的加热搅拌时间为1～3小时。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的加热搅拌时间为2小时。
在本申请的一些实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的降温搅拌时间为2～20小时；优选地，精制步骤(c)中所述的降温搅拌时间为2～15小时；进一步优选地，精制步骤(c)中所述的降温搅拌时间为5～15小时。在本申请的一个具体的实施方案中，对于所述中间体化合物6的制备方法，其中精制步骤(c)中所述的降温搅拌时间为6小时。
另一方面，本申请提供一种式II化合物的制备方法，所述制备方法包括：式IV化合物和式III化合物在还原剂和溶剂的存在下反应，得到式II化合物。
Figure PCTCN2022138020-appb-000003
在本申请的一些实施方案中，所述式II化合物的制备方法中的还原剂选自甲酸、甲酸/钯碳、甲酸铵/钯碳、水合肼/钯碳、雷尼镍/水合肼、三乙酰氧基硼氢化钠、硼氢化钠、FeOOH/水合肼、FeOOH/活性炭/水合肼、FeCl 3/水合肼或FeCl 3/活性炭/水合肼；优选地，所述还原剂选自三乙酰氧基硼氢化钠、硼氢化钠、雷尼镍/水合肼或FeOOH/水合肼；进一步优选地，所述还原剂选自三乙酰氧基硼氢化钠或硼氢化钠。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的还原剂选自三乙酰氧基硼氢化钠。
在本申请的一些实施方案中，所述式II化合物的制备方法中的还原剂可任选地在催化剂存在条件下使用，所述催化剂选自甲酸、乙酸、酒石酸、富马酸、马来酸、柠檬酸、盐酸、碳酸、草酸、氢氟酸、苹果酸、苯甲酸、三氟乙酸、氯化氢、胍盐酸盐、吡啶对甲苯磺酸盐、四氯化钛、钛酸四异丙酯或氯化锌；优选地，所述催化剂选自甲酸、乙酸、富马酸、酒石酸、马来酸；进一步优选地，所述催化剂选自甲酸或乙 酸。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的还原剂在催化剂存在条件下使用，所述催化剂选自乙酸。
在本申请的一些实施方案中，所述式II化合物的制备方法中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、乙醚、甲基叔丁基醚、乙酸乙酯、乙酸丁酯、四氢呋喃、2-甲基四氢呋喃、正庚烷、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或多种混合的溶剂；优选地，所述溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、甲苯、甲基叔丁基醚、2-甲基四氢呋喃、正庚烷中的一种或多种混合的溶剂；进一步优选地，所述溶剂选自二氯甲烷、甲苯、甲醇、甲基叔丁基醚中的一种或多种混合的溶剂。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中所述的溶剂选自二氯甲烷。
在本申请的一些实施方案中，所述式II化合物的制备方法中的式III化合物与式IV化合物的摩尔比为1:(1～3)；优选地，式III化合物与式IV化合物的摩尔比为1:(1～2)；进一步优选地，式III化合物与式IV化合物的摩尔比为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。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的式III化合物与式IV化合物的摩尔比为1:1.1。
在本申请的一些实施方案中，所述式II化合物的制备方法中的式III化合物与还原剂的摩尔比为1:(1～5)；优选地，式III化合物与还原剂的摩尔比为1:(1～3)；进一步优选地，式III化合物与还原剂的摩尔比为1:1、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2、1:2.5、1:3。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的式III化合物与还原剂的摩尔比为1:2。
在本申请的一些实施方案中，所述式II化合物的制备方法中的式III化合物与催化剂的摩尔比为1:(0.01～1)；优选地，式III化合物与催化剂的摩尔比为1:(0.05～1)；进一步优选地，式III化合物与催化剂的摩尔比为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。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的式III化合物与催化剂的摩尔比为1:0.2。
在本申请的一些实施方案中，所述式II化合物的制备方法中的式III化合物与溶剂的摩尔体积比为1mmol:(1～10mL)；优选地，式III化合物与溶剂的摩尔体积比为1mmol:(1～5mL)；进一步优选地，式III化合物与溶剂的摩尔体积比为1mmol:(2～4mL)；更进一步优选地，式III化合物与溶剂的摩尔体积比为1mmol:2mL、1mmol:2.5mL、1mmol:3mL、1mmol:3.1mL、1mmol:3.2mL、1mmol:3.3mL、1mmol:3.4mL、1mmol:3.5mL、1mmol:3.6mL、1mmol:3.7mL、1mmol:3.8mL、1mmol:3.9mL、1mmol:4mL。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的式III化合物与溶剂的摩尔体积比为1mmol:3.4mL。
在本申请的一些实施方案中，所述式II化合物的制备方法中的反应温度为10℃～50℃；优选地，所述反应温度为10℃～30℃；进一步优选地，所述反应温度为20℃～35℃。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的反应温度为25℃～35℃。
在本申请的一些实施方案中，所述式II化合物的制备方法中的反应时间为2～24小时；优选地，所述反应时间为5～20小时；进一步优选地，所述反应时间为5～15小时。在本申请的一个具体的实施方案中，所述式II化合物的制备方法中的反应时间为10小时。
另一方面，本申请提供一种式(I)化合物的制备方法，所述制备方法包括：(1)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6；(2)中间体化合物6与化合物7在溶剂和碱存在下反应，得到化合物8；(3)化合物8和化合物9在溶剂和酸存在下反应，得到式(I)化合物。
Figure PCTCN2022138020-appb-000004
其中，在所述式(I)化合物的制备方法中，步骤(1)的条件如上述的中间体化合物6的制备方法的步骤(a)。
在本申请的一些实施方案中，所述式(I)化合物的制备方法进一步包括：(1’)向步骤(1)的反应体系中进一步加入溶剂搅拌，过滤，得到纯化的中间体化合物6。其中，所述步骤(1’)的条件如上述的中间体化合物6的制备方法的步骤(b)。
在本申请的一些实施方案中，所述式(I)化合物的制备方法进一步包括中间体化合物6的精制步骤(1”)：将步骤(1’)过滤得到的中间体化合物6进一步与溶剂加热搅拌，再降温搅拌，过滤，得到精制的中间体化合物6。其中，所述中间体化合物6的精制步骤(1”)的条件如上述的中间体化合物6的制备方法的步骤(c)。
在本申请的一些实施方案中，所述式(I)化合物的制备方法的步骤(2)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、四氢呋喃、2-甲基四氢呋喃、乙腈、DMF、DMAC或DMSO中的一种或多种混合的溶剂；优选地，步骤(2)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、乙腈中的一种或多种混合的溶剂；进一步优选地，步骤(2)中所述的溶剂选自甲醇、乙醇、乙腈中的一种；在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法的步骤(2)中所述的溶剂选自乙腈。
在本申请的一些实施方案中，所述式(I)化合物的制备方法的步骤(2)中所述的碱选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸钙、三乙胺、吡啶、三乙醇胺、氢氧化钠、氢氧化钾或氢氧化钙中的一种或几种；优选地，步骤(2)中所述的碱选自碳酸钠、碳酸钾、碳酸钙、氢氧化钠、氢氧化钾或氢氧化钙中的一种或几种；进一步优选地，步骤(2)中所述的碱选自碳酸钠、碳酸钾或碳酸钙中的一种；在本申请的一个具体实施方案中，所述式(I)化合物的制备方法的步骤(2)中所述的碱选自碳酸钠。
在本申请的一些实施方案中，所述式(I)化合物的制备方法的步骤(2)中，中间体化合物6与化合物7的摩尔比为1:(1～3)；优选地，中间体化合物6与化合物7的摩尔比为1:(1～1.5)；进一步优选地，中间体化合物6与化合物7的摩尔比为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。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法的步骤(2)中，中间体化合物6与化合物7的摩尔比为1:1.05。
在本申请的一些实施方案中，所述式(I)化合物的制备方法的步骤(2)中，中间体化合物6与碱的摩尔比为1:(1～8)；优选地，中间体化合物6与碱的摩尔比为1:(1～5)；进一步优选地，中间体化合物6与 碱的摩尔比为1:1、1:2、1:3、1:4、1:5。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法的步骤(2)中，中间体化合物6与碱的摩尔比为1:3。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(2)的反应温度为50℃～120℃；优选地，反应温度为80℃～120℃；进一步优选地，反应温度为80℃～100℃。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(2)的反应温度为80℃～90℃。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(2)的反应时间为2～24小时；优选地，反应时间为10～24小时；进一步优选地，反应时间为10～20小时。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(2)的反应时间为16小时。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(2)进一步包括：(2’)向步骤(2)得到的化合物8加入溶剂搅拌，过滤，滤饼用打浆溶剂搅拌洗涤，过滤，滤饼烘干得到精制的化合物8。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(2’)中所述的溶剂选自水、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、四氢呋喃、2-甲基四氢呋喃或乙腈中的一种或多种混合的溶剂；优选地，步骤(2’)中所述的溶剂选自水。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(2’)中所述的打浆溶剂选自甲基叔丁基醚、乙醚、乙酸乙酯、二氯甲烷中的一种或多种混合的溶剂；优选地，步骤(2’)中所述的打浆溶剂选自甲基叔丁基醚。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、四氢呋喃、2-甲基四氢呋喃、乙腈、DMF、DMAC或DMSO中的一种或多种混合的溶剂；优选地，步骤(3)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、乙腈中的一种或多种混合的溶剂；进一步优选地，步骤(3)中所述的溶剂选自甲醇、乙醇、1,4-二氧六环、乙腈中的一种；在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(3)所述的溶剂选自1,4-二氧六环。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)中所述的酸选自对甲苯磺酸、三氟乙酸、三氟甲磺酸、甲磺酸、氢氟酸、甲酸、乙酸、丙酸、丁酸、戊酸、盐酸、磷酸或硫酸的一种或几种；优选地，步骤(3)中所述的酸选自对甲苯磺酸、三氟乙酸、三氟甲磺酸或甲磺酸的一种或几种；进一步优选地，步骤(3)中所述的酸选自对甲苯磺酸、三氟乙酸中的一种；在本申请的一个具体实施方案中，所述式(I)化合物的制备方法中步骤(3)所述的酸选自对甲苯磺酸。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)的化合物8与化合物9的摩尔比为1:(1～3)；优选地，化合物8与化合物9的摩尔比为1:(1～1.5)；进一步优选地，化合物8与化合物9的摩尔比为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。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(3)的化合物8与化合物9的摩尔比为1:1.05。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)的化合物8与酸的摩尔比为1:(1～8)；优选地，化合物8与酸的摩尔比为1:(1～5)；进一步优选地，化合物8与酸的摩尔比为1:1、1:2、1:3、1:4、1:5。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(3)的化合物8与酸的摩尔比为1:3。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)的反应温度为50℃～120℃；优选地，反应温度为80℃～120℃；进一步优选地，反应温度为90℃～110℃。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(3)的反应温度为95℃～105℃。
在本申请的一些实施方案中，所述式(I)化合物的制备方法中步骤(3)的反应时间为2～24小时；优选地，反应时间为10～24小时；进一步优选地，反应时间为10～20小时。在本申请的一个具体的实施方案中，所述式(I)化合物的制备方法中步骤(3)的反应时间为16小时。
另一方面，本申请提供了一种式(I)化合物的制备方法，所述制备方法包括：(i)式IV化合物和式III化合物在还原剂和溶剂的存在下反应，得到式II化合物；(ii)式II化合物在盐酸和溶剂的存在下反应， 得到中间体化合物6；(iii)中间体化合物6与化合物7在溶剂和碱存在下反应，得到化合物8；(iv)化合物8和化合物9在溶剂和酸存在下反应，得到式(I)化合物。
Figure PCTCN2022138020-appb-000005
其中，所述式(I)化合物的制备方法中，步骤(i)、步骤(ii)、步骤(iii)和步骤(iv)的条件分别如上式II化合物的制备方法、中间体化合物6的制备方法步骤(a)、式(I)化合物的制备方法步骤(2)和式(I)化合物的制备方法步骤(3)所述。
在本申请的一些实施方案中，所述式(I)化合物的制备方法进一步包括：(ii’)向步骤(ii)的反应体系中进一步加入溶剂搅拌，过滤，得到纯化的中间体化合物6。其中，所述步骤(ii’)的条件如上述的中间体化合物6的制备方法的步骤(b)。
在本申请的一些实施方案中，所述式(I)化合物的制备方法进一步包括中间体化合物6的精制步骤(ii”)：将步骤(ii’)过滤得到的中间体化合物6进一步与溶剂加热搅拌，再降温搅拌，过滤，得到精制的中间体化合物6。其中，所述中间体化合物6的精制步骤(ii”)的条件如上中间体化合物6的制备方法的步骤(c)所述。
另一方面，本申请还提供一种式IV化合物的制备方法，所述式IV化合物的制备方法包括：式VI化合物和式V化合物在溶剂存在下反应，得到式IV化合物。
Figure PCTCN2022138020-appb-000006
在本申请的一些实施方案中，所述式IV化合物的制备方法中的溶剂选自水、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、四氢呋喃、2-甲基四氢呋喃、乙腈、DMF、DMAC或DMSO中的一种或多种混合的溶剂；优选地，所述溶剂选自水、甲醇、乙醇、异丙醇、四氢呋喃、乙腈中的一种或多种混合的溶剂；进一步优选地，所述溶剂选自水、甲醇、乙醇或异丙醇中的一种或多种混合的溶剂。在本申请的一个具体的实施方案中，所述式IV化合物的制备方法中，所述溶剂选自水。
在本申请的一些实施方案中，所述式IV化合物的制备方法中，式VI化合物与式V化合物的摩尔比为1:(1～3)；优选地，式VI化合物与式V化合物的摩尔比为1:(1～1.5)；进一步优选地，式VI化合物与式V化合物的摩尔比为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。在本申请的一个具体的实施方案中，所述式IV化合物的制备方法中，式VI化合物与式V化合物的摩尔比为1:1.1。
在本申请的一些实施方案中，所述式IV化合物的制备方法中式VI化合物与溶剂的摩尔体积比为(1～5mmol):1mL；优选地，式VI化合物与溶剂的摩尔体积比为(2～4mmol):1mL；进一步优选地，式VI化合物与溶剂的摩尔体积比为2mmol:1mL、2.5mmol:1mL、3mmol:1mL、3.5mmol:1mL、4mmol:1mL。在本申请的一个具体的实施方案中，所述式IV化合物的制备方法中式VI化合物与溶剂的摩尔体积比为3mmol:1mL。
在本申请的一些实施方案中，所述式IV化合物的制备方法中反应温度为10℃～50℃；优选地，反应温度为10℃～40℃；进一步优选地，反应温度为20℃～40℃。在本申请的一个具体的实施方案中，所述式IV化合物的制备方法中反应温度为20℃～30℃。
在本申请的一些实施方案中，所述式IV化合物的制备方法中反应时间为2～24小时；优选地，反应时间为10～24小时；进一步优选地，反应时间为10～20小时。在本申请的一个具体的实施方案中，式IV化合物的制备方法中反应时间为12小时。
本申请还提供了一种中间体化合物6的制备方法用于制备式(I)化合物的用途，所述中间体化合物6的制备方法包括：(a)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6。
Figure PCTCN2022138020-appb-000007
其中，步骤(a)的条件如上所述。
本申请还提供了一种制备式(I)化合物的方法，所述方法包括；根据本申请的上述方法由式II化合物制备中间体化合物6，并进一步制备式(I)化合物。
所述制备式(I)化合物的方法还进一步包括以下步骤：根据本申请的上述方法由式IV化合物和式III化合物制备式II化合物的步骤，和/或根据本申请的上述方法由式VI化合物和式V化合物制备式IV化合物的步骤。
技术效果
本发明的制备方法，相比已知的通过液相分离反式异构体或直接用昂贵的反式异构体原料而言，通过式II化合物在盐酸和特定溶剂的条件下反应后就能够直接制备得到高纯度反式异构体中间体化合物6，所得产物便于后续进一步纯化，其具有反应条件温和、反应步骤短、反应时间短、后处理操作简单、异构体纯度高等优点，非常适合工业化生产。
术语及定义
本申请所述的“DMF”为N,N-二甲基甲酰胺。
本申请所述的“DMAC”为N,N-二甲基乙酰胺。
本申请所述的“DMSO”为二甲基亚砜。
本申请所述的“MTBE”为甲基叔丁基醚。
本申请所述的酸和碱包括无水形式和水合物形式。
术语“盐酸”包括氯化氢气体和氯化氢溶液，所述氯化氢溶液包括水溶液和有机溶剂溶液。
术语“浓盐酸”是指氯化氢质量分数超过20％的氯化氢水溶液。例如，浓盐酸的浓度可为36％-38％，即氯化氢质量分数为36％-38％的氯化氢水溶液。
本申请所述的式VI化合物、式V化合物、式IV化合物、式III化合物、化合物7、化合物9均可经商业购买途径获得。
本申请所述的式IV化合物还可通过上述式IV化合物的制备方法，由式VI化合物和式V化合物在溶剂存在下制备得到。
本申请所述的化合物7和化合物9也可通过WO2020001449公开的方法制备得到。
除非另有定义，否则本文所有科技术语具有的涵义与所声称的主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。如果引用的是URL或其它这种标识符或地址，应理解这种标识符会改变，因特网上的特定信息来去自由，但是通过搜索因特网或其它合适的参考资源可以找到相应的信息。这里引用表明这些信息的可获得和公开传播。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对所声称主题作任何限制。在本申请中，除非另有特别说明，否则使用单数时也包括复数。应注意的是，除非上下文明确指示，否则在说明书和所附权利要求书中使用的单数形式“一个/一种(a/an)”和“所述/该(the)”包括复数形式。还应注意，除非另有说明，否则所用“或”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”、“含有”和“具有”并非限制性。
本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着对本申请有任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
实施例1：式IV化合物的制备
Figure PCTCN2022138020-appb-000008
于100mL反应瓶中加入5.0g式VI化合物、20mL水，35～40℃搅拌溶解，溶解后温度降至25℃，加入5.8g式V化合物，20～30℃反应12小时。反应结束后用浓盐酸调pH＝1，用二氯甲烷分三次(3×6mL)洗涤，水相用30wt％氢氧化钠溶液调pH＝9.8，水相加入5.0g氯化钠搅拌至溶解，用二氯甲烷分三次(3×20mL)萃取，有机相经无水硫酸钠干燥，过滤，合并有机相减压浓缩，得式IV化合物4.1g。
ESI-MS:m/z＝145.1[M+H] +
实施例2：式II化合物的制备
Figure PCTCN2022138020-appb-000009
于1L反应瓶中加入30.0g式III化合物、21.9g式IV化合物、1.7g乙酸、480mL二氯甲烷，25～35℃搅拌，后加入59.6g(均分两次，每隔半小时加一次)三乙酰氧基硼氢化钠，25～35℃搅拌反应10小时，TLC监测(二氯甲烷：甲醇＝10:1，磷钼酸显色)至原料反应完全。反应液用5N氢氧化钠溶液调pH＝7.5， 过滤，滤液用5％碳酸钠溶液(2×300mL)洗涤两次，收集有机相待用。合并水相，用二氯甲烷萃取一次(300mL)，合并所有有机相，经无水硫酸钠干燥，过滤，滤液30±5℃减压浓缩至干。浓缩物用360mL正庚烷：甲基叔丁基醚＝5:1混合溶剂搅拌洗涤12小时，过滤，滤液45±5℃减压干燥6小时，得41.1g式II化合物，顺式异构体：反式异构体＝1.09:1。
氢谱： 1H NMR(400MHz,CDCl 3)δ4.37(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＝11.60Hz,2H),1.87(d,J＝12.40Hz,2H),1.44(s,9H),1.28-1.38(m,2H),1.09-1.13(m,2H)。
实施例3-1：中间体化合物6的制备
Figure PCTCN2022138020-appb-000010
于100mL反应瓶中加入41.0g式II化合物、205mL丙酮，25～30℃搅拌均匀，加入59.2g浓盐酸，25～30℃搅拌反应5小时，TLC检测(二氯甲烷：甲醇＝10:1，磷钼酸显色)至原料反应完全，得到中间体化合物6纯度为96.4％。加入410mL丙酮和144ml乙醇，室温搅拌12小时，过滤，滤饼用169mL乙醇/丙酮＝1:1打浆混合溶剂于45～50℃加热2小时后缓慢降温至5～15℃，搅拌6小时以上，过滤，滤饼50±5℃减压干燥6小时，得16.1g中间体化合物6，纯度99.08％。
氢谱： 1H NMR(400MHz,CD 3OD)δ4.27-4.30(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)。
参照实施例3-1制备中间体化合物6的方法一，将打浆混合溶剂替换成表1中的溶剂，其中溶剂为体积比：
表1
打浆溶剂 中间体化合物6纯度
乙醇 99.22％
丙酮 95.45％
乙醇：丙酮＝1:2 98.28％
乙醇：丙酮＝1:3 97.24％
乙醇：丙酮＝1:4 96.26％
甲醇：MTBE＝1:0.5 94.91％
甲醇：MTBE＝1:0.75 92.40％
甲醇：MTBE＝1:1 96.58％
甲醇：MTBE＝1:1.5 96.35％
甲醇：MTBE＝1:2 95.24％
甲醇：MTBE＝1:2(甲醇先加入，与MTBE间隔30分钟) 97.13％
实施例3-2：中间体化合物6的制备
Figure PCTCN2022138020-appb-000011
于100mL反应瓶中加入41.0g式II化合物、205mL丙酮，25～30℃搅拌均匀，加入59.2g浓度为36％-38％的浓盐酸，25～30℃搅拌反应5小时，TLC检测(二氯甲烷：甲醇＝10:1，磷钼酸显色)至原料反应完全。加入410mL丙酮和144mL乙醇，室温搅拌12小时，过滤，滤饼用56mL甲醇于45～50℃加热30分钟，缓慢加入112mL甲基叔丁基醚，打浆2小时后缓慢降温至5～15℃，搅拌6小时以上，过滤，滤饼50±5℃减压干燥6小时，得15.5g中间体化合物6，纯度97.13％。
实施例3-3：中间体化合物6的制备
Figure PCTCN2022138020-appb-000012
于100mL反应瓶中加入41.0g式II化合物、205mL丙酮，25～30℃搅拌均匀，加入59.2g浓度为36％-38％的浓盐酸，25～30℃搅拌反应5小时，TLC检测(二氯甲烷：甲醇＝10:1，磷钼酸显色)至原料反应完全。加入410mL丙酮和144mL乙醇，室温搅拌12小时，过滤，滤饼用169mL乙醇/丙酮＝2:1打浆混合溶剂于45～50℃加热2小时后缓慢降温至5～15℃，搅拌6小时以上，过滤，滤饼50±5℃减压干燥6小时，得14.7g中间体化合物6，纯度98.28％。
实施例4：式(I)化合物的制备
Figure PCTCN2022138020-appb-000013
参照实施例1制备式IV化合物；
参照实施例2制备式II化合物；
参照实施例3制备中间体化合物6；
化合物8的制备：
搅拌下于反应罐中加入将53L乙腈、2.65kg化合物7、3.59kg中间体化合物6，分批次加入无水碳酸钠共计3.83kg，升温至80～90℃，搅拌反应16小时后取样TLC跟踪监控至反应终点。反应结束后，降温 至20～30℃，向反应罐中加入纯化水搅拌1小时，过滤，滤饼用甲基叔丁基醚于20～30℃搅拌洗涤，过滤，滤饼于45±5℃烘干得到4.11kg化合物8。
氢谱：1H NMR(400MHz,DMSO-d6)δ7.00(d,J＝8.00Hz,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＝12.00Hz,2H),1.65-1.52(m,2H),1.44-1.31(m,2H).ESI-MS：m/z＝425.2[M+H]+。
式(I)化合物的制备：
于反应罐中加入1,4-二氧六环40.7L、4.07Kg化合物8、1.68kg化合物9、对甲苯磺酸一水合物5.47kg，升温至95～105℃，搅拌反应16小时后取样TLC跟踪监控至反应终点。反应结束后，降温至30～40℃，向反应罐中加入纯化水40.7L和甲基叔丁基醚40.7L搅拌15分钟，分液；水相用甲基叔丁基醚萃取，分液；水相加入1mol/L氢氧化钠溶液至pH≈11～13，过滤；滤饼用0.1mol/L氢氧化钠溶液搅拌洗涤，过滤；滤饼用纯化水均分4次搅拌洗涤，过滤；滤饼用乙腈水溶液搅拌洗涤，过滤；滤饼于45±5℃烘干得到4.60kg式(I)化合物。
氢谱：1H NMR(400MHz,DMSO-d 6)δ7.76(brs,1H),δ7.59(brs,1H),δ4.38(m,1H),δ3.92(m,1H),δ3.34(m,1H),δ4.24(m,2H),δ3.51(m,2H),δ3.24(m,2H),δ3.13(m,2H),δ4.02(m,2H),δ3.57(m,2H),δ2.01(m,2H),δ1.92(m,2H),δ2.21(m,2H),δ2.19(m,4H),δ1.58(m,2H),δ3.67(s,3H),δ2.54(s,3H).ESI-MS：m/z＝628.62[M+H] +。
实施例5：式(I)化合物盐酸盐的制备
Figure PCTCN2022138020-appb-000014
于反应罐中加入无水甲醇68.1L、式(I)化合物，控温25℃以下缓慢加入氯化氢/甲醇溶液，加毕，控温20～30℃，搅拌16小时。向反应液中加入无水甲醇22.7L搅拌，过滤，滤饼用无水甲醇均分2次淋洗，过滤。滤饼用无水甲醇于回流搅拌洗涤，降温，过滤，滤饼用无水甲醇和甲基叔丁基醚混合溶液均分2次淋洗，过滤；滤饼于45±5℃烘干、粉碎得到4.078kg式(I)化合物的盐酸盐。

Claims (20)

  1. 一种中间体化合物6的制备方法，包括：
    (a)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6；
    Figure PCTCN2022138020-appb-100001
  2. 根据权利要求1所述的中间体化合物6的制备方法，其中步骤(a)中所述的盐酸选自浓盐酸、盐酸/甲醇溶液、盐酸/乙酸乙酯溶液、盐酸/丙酮溶液、盐酸/乙醇溶液、氯化氢/乙酸乙酯溶液、氯化氢/甲醇溶液、氯化氢/乙醇溶液或氯化氢/二氧六环溶液。
  3. 根据权利要求1所述的中间体化合物6的制备方法，其中步骤(a)中所述的溶剂选自乙醇、丙酮、甲基叔丁基醚中的一种。
  4. 根据权利要求1所述的中间体化合物6的制备方法，其中步骤(a)中式II化合物与氯化氢的摩尔比为1:1～10。
  5. 根据权利要求1所述中间体化合物6的制备方法，其中步骤(a)中式II化合物与步骤(a)中所述的溶剂的摩尔体积比为1mmol:(1～5mL)。
  6. 根据权利要求1所述的中间体化合物6的制备方法，其中进一步包括：(b)向步骤(a)的反应体系中进一步加入溶剂搅拌，过滤，得到纯化的中间体化合物6。
  7. 根据权利要求6所述的中间体化合物6的制备方法，其中步骤(b)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、乙醚、甲基叔丁基醚、乙酸乙酯、乙酸丁酯、四氢呋喃、2-甲基四氢呋喃、正庚烷、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或多种混合的溶剂。
  8. 根据权利要求7所述的中间体化合物6的制备方法，其中步骤(b)中所述的溶剂选自甲醇、乙醇、异丙醇、正丁醇、丙酮、甲基叔丁基醚、乙腈中的任意两种溶剂的混合溶剂。
  9. 根据权利要求8所述的中间体化合物6的制备方法，其中步骤(b)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述混合溶剂中所述乙醇和丙酮的体积比为1:(0.5～10)。
  10. 根据权利要求8所述的中间体化合物6的制备方法，其中步骤(b)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；所述混合溶剂中所述甲醇和甲基叔丁基醚的体积比为1:(0.5～10)。
  11. 根据权利要求6所述的中间体化合物6的制备方法，其中步骤(b)中所述的溶剂与步骤(a)中式II化合物的体积质量比为(2～20mL):1g。
  12. 根据权利要求6所述的中间体化合物6的制备方法，其中进一步包括中间体化合物6的精制步骤(c)：将步骤(b)过滤得到的中间体化合物6进一步与溶剂加热搅拌，再降温搅拌，过滤，得到精制的中间体化合物6。
  13. 根据权利要求12所述的中间体化合物6的制备方法，其中中间体化合物6的精制步骤(c)中所述的溶剂选自水、二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、1,4-二氧六环、丙酮、乙醚、甲基叔丁基醚、乙酸乙酯、乙酸丁酯、四氢呋喃、2-甲基四氢呋喃、正庚烷、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或多种混合的溶剂。
  14. 根据权利要求13所述的中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自乙醇和丙酮的混合溶剂；所述混合溶剂中所述乙醇和丙酮的体积比为1:(0.5～10)。
  15. 根据权利要求13所述的中间体化合物6的制备方法，其中精制步骤(c)中所述的溶剂选自甲醇和甲基叔丁基醚的混合溶剂；所述混合溶剂中所述甲醇和甲基叔丁基醚的体积比为1:(0.5～10)。
  16. 一种式(I)化合物的制备方法，所述制备方法包括：(1)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6；(2)中间体化合物6与化合物7在溶剂和碱存在下反应，得到化合物8；(3)化合物8和化合物9在溶剂和酸存在下反应，得到式(I)化合物；
    Figure PCTCN2022138020-appb-100002
    其中，步骤(1)的条件如权利要求1-5中任一项所述。
  17. 根据权利要求1所述的中间体化合物6的制备方法，其中式II化合物的制备方法包括：式IV化合物和式III化合物在还原剂和溶剂的存在下反应，得到式II化合物；
    Figure PCTCN2022138020-appb-100003
  18. 根据权利要求17所述的中间体化合物6的制备方法，其中式IV化合物的制备方法包括：式VI化合物和式V化合物在溶剂存在下反应，得到式IV化合物；
    Figure PCTCN2022138020-appb-100004
  19. 一种式(I)化合物的制备方法，所述制备方法包括：(i)式IV化合物和式III化合物在还原剂和溶剂的存在下反应，得到式II化合物；(ii)式II化合物在盐酸和溶剂的存在下反应，得到中间体化合物6；(iii)中间体化合物6与化合物7在溶剂和碱存在下反应，得到化合物8；(iv)化合物8和化合物9在溶剂和酸存在下反应，得到式(I)化合物；
    Figure PCTCN2022138020-appb-100005
    其中，所述式(I)化合物的制备方法中，步骤(i)、步骤(ii)、步骤(iii)和步骤(iv)的条件分别如权利要求17所述的式II化合物的制备方法、权利要求1-5中任一项所述的中间体化合物6的制备方法步骤(a)、权利要求16所述的式(I)化合物的制备方法步骤(2)和权利要求16所述的式(I)化合物的制备方法步骤(3)所述。
  20. 权利要求1-15所述的中间体化合物6的制备方法用于制备式(I)化合物的用途。
PCT/CN2022/138020 2021-12-10 2022-12-09 一种异噻唑并[5,4-d]嘧啶类IRAK4抑制剂的制备方法 WO2023104195A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN102627653A (zh) * 2012-03-20 2012-08-08 南京臣功制药股份有限公司 盐酸伊立替康的制备方法
WO2021147968A1 (zh) * 2020-01-21 2021-07-29 正大天晴药业集团股份有限公司 一种irak4抑制剂的结晶及其制备方法
WO2021194318A1 (en) * 2020-03-27 2021-09-30 Uppthera Plk1 selective degradation inducing compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627653A (zh) * 2012-03-20 2012-08-08 南京臣功制药股份有限公司 盐酸伊立替康的制备方法
WO2021147968A1 (zh) * 2020-01-21 2021-07-29 正大天晴药业集团股份有限公司 一种irak4抑制剂的结晶及其制备方法
WO2021194318A1 (en) * 2020-03-27 2021-09-30 Uppthera Plk1 selective degradation inducing compound

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