WO2023201780A1 - 喹诺酮类化合物及其中间体的制备方法 - Google Patents

喹诺酮类化合物及其中间体的制备方法 Download PDF

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WO2023201780A1
WO2023201780A1 PCT/CN2022/090989 CN2022090989W WO2023201780A1 WO 2023201780 A1 WO2023201780 A1 WO 2023201780A1 CN 2022090989 W CN2022090989 W CN 2022090989W WO 2023201780 A1 WO2023201780 A1 WO 2023201780A1
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optionally substituted
alkyl
compound
formula
independently selected
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PCT/CN2022/090989
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French (fr)
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雷杰
陈中祝
徐志刚
唐典勇
徐迦渝
周昊亿
夏丹丹
刘垚
曹艺华
罗洁
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重庆文理学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • 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
    • C07D513/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application relates to the field of medicinal chemistry. Specifically, this application relates to the preparation method of quinolone compounds and their intermediates (such as quinolone compounds), especially the preparation method of quinolone and quinolinone pharmaceutical intermediates.
  • quinolones are widely used in clinical antibacterial, anticancer and cystic fibrosis treatments. They have many advantages such as broad antibacterial spectrum, strong medicinal activity, low toxicity and high efficacy.
  • Ethyl benzoacetate is used as the starting material. It first reacts with triethyl orthoformate and condenses with aliphatic amine to form the compound enamine dicarbonyl compound. After an intramolecular nucleophilic substitution reaction occurs under alkaline conditions, a cyclization intermediate is obtained, and finally the quinolone intermediate is obtained by hydrolysis under HCl conditions.
  • the raw material of 2-fluorobenzoyl ethyl acetate is expensive, and the acetal reagent: triethyl orthoformate is a liquid with an irritating odor, has a low melting and boiling point, and is difficult to store.
  • the application provides a method for preparing a compound of formula I, which includes the following steps:
  • X is selected from CR 2 or N;
  • Z is selected from CR 4 or N;
  • R 1 is independently selected from hydrogen, alkyl, alkoxy, halogen, NO 2 , CN, optionally substituted amino, haloalkyl, aryl and heteroaryl;
  • R 2 and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl; or R 2 and R 3 are joined together to form a ring ;
  • R 4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl;
  • R 5 is independently selected from alkyl optionally substituted by OH or SH, cycloalkyl optionally substituted by halogen, aryl and heteroaryl;
  • R 6 is independently selected from sulfonyl.
  • the application provides a method for preparing a compound of formula I, which includes the following steps:
  • step ii) wherein the reaction of step ii) is carried out at a temperature higher than the reaction temperature of step i);
  • X is selected from CR 2 or N;
  • Z is selected from CR 4 or N;
  • R 1 is independently selected from hydrogen, alkyl, alkoxy, halogen, NO 2 , CN, optionally substituted amino, haloalkyl, aryl and heteroaryl;
  • R 2 and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl; or R 2 and R 3 are joined together to form a ring ;
  • R 4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl;
  • R 5 is independently selected from alkyl optionally substituted by OH or SH, cycloalkyl optionally substituted by halogen, aryl and heteroaryl;
  • R 6 is independently selected from sulfonyl.
  • the application provides a method for preparing a compound of formula II, which includes the following steps:
  • the compound of formula I is prepared by the method described in the first or second aspect above;
  • the compound of formula I is oxidized to form the compound of formula II,
  • the application provides a method for preparing a compound of formula III, which includes the following steps:
  • the compound of formula II is prepared by the method described in the third aspect above.
  • the compound of formula II is reacted with an optionally substituted nitrogen-containing heterocyclic compound in the presence of a base to generate the compound of formula III, or the compound of formula II is subjected to Stille coupling reaction to generate the compound of formula III,
  • R 2 and R 3 do not form a ring and R 3 is halogen
  • the application provides a method for preparing a compound of formula IV, which includes the following steps:
  • the compound of formula II is prepared by the method described in the third aspect above.
  • Z is CR 4 , R 4 is halogen or amino and R 5 is OH or SH substituted alkyl;
  • the application provides a method for preparing a compound of formula I, which includes the following steps:
  • X is selected from CR 2 or N;
  • Z is selected from CR 4 or N;
  • R 1 is independently selected from hydrogen, alkyl, alkoxy, halogen, NO 2 , CN, optionally substituted amino, haloalkyl, aryl and heteroaryl;
  • R 2 and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl; or R 2 and R 3 are joined together to form a ring ;
  • R 4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl;
  • R 5 is independently selected from alkyl optionally substituted by OH or SH, cycloalkyl optionally substituted by halogen, aryl and heteroaryl;
  • R 6 is independently selected from sulfonyl.
  • the base is selected from inorganic bases, organic bases, and combinations thereof.
  • the base is selected from primary amines.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium tert-butoxide, sodium methoxide, sodium bicarbonate, sodium hydrogen, triethylamine, diisopropylamine, diisopropylamine, Azabicyclo (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and combinations thereof.
  • the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, and combinations thereof.
  • the reaction is performed in a solvent.
  • the reaction is performed in a reaction medium selected from the group consisting of methanol, ethanol, acetonitrile, toluene, water, N,N-dimethylformamide, xylene, nitrobenzene, trifluorotoluene, N-methylpyrrolidone, 1 ,2-dichloroethane, 1,4-dioxane, and their combinations in solvents.
  • a reaction medium selected from the group consisting of methanol, ethanol, acetonitrile, toluene, water, N,N-dimethylformamide, xylene, nitrobenzene, trifluorotoluene, N-methylpyrrolidone, 1 ,2-dichloroethane, 1,4-dioxane, and their combinations in solvents.
  • the reaction is performed in a solvent selected from N,N-dimethylformamide, N-methylpyrrolidone, and combinations thereof.
  • the reaction is performed at 80°C to 200°C (e.g., 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C) or 100°C-150°C.
  • 80°C 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C
  • 100°C-150°C e.g., 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C
  • the application provides a method for preparing a compound of formula I, which includes the following steps:
  • step ii) wherein the reaction of step ii) is carried out at a temperature higher than the reaction temperature of step i);
  • X is selected from CR 2 or N;
  • Z is selected from CR 4 or N;
  • R 1 is independently selected from hydrogen, alkyl, alkoxy, halogen, NO 2 , CN, optionally substituted amino, haloalkyl, aryl and heteroaryl;
  • R 2 and R 3 are each independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl; or R 2 and R 3 are joined together to form a ring ;
  • R 4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl and heteroaryl;
  • R 5 is independently selected from alkyl optionally substituted by OH or SH, cycloalkyl optionally substituted by halogen, aryl and heteroaryl;
  • R 6 is independently selected from sulfonyl.
  • the base in step i) is selected from the group consisting of inorganic bases, organic bases, and combinations thereof. In some embodiments, the base in step i) is selected from primary amines, preferably an excess of primary amines.
  • the base in step i) is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium tert-butoxide, sodium methoxide, sodium bicarbonate, sodium hydrogen, triethylamine, diisobutoxide Propylamine, diazabicyclo, 1,4-diazabicyclo[2.2.2]octane, and combinations thereof.
  • the base in step i) is selected from the group consisting of lithium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylamine, diazabicyclo, and combinations thereof.
  • reaction of step i) is performed in a first solvent.
  • the reaction of step i) is carried out in a reaction medium selected from the group consisting of methanol, ethanol, acetonitrile, toluene, water, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane and their combinations in the first solvent.
  • a reaction medium selected from the group consisting of methanol, ethanol, acetonitrile, toluene, water, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane and their combinations in the first solvent.
  • the reaction of step i) is performed at room temperature to 150°C (e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C or 150°C ) or at room temperature to 100°C.
  • 150°C e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°
  • the base in step ii) is selected from inorganic bases.
  • the base in step ii) is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium tert-butoxide, sodium methoxide, sodium bicarbonate, sodium hydrogen, and combinations thereof.
  • the base in step ii) is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, and combinations thereof.
  • reaction of step ii) is performed in a second solvent, wherein the second solvent and the first solvent may be the same or different.
  • the reaction of step ii) is performed in a reaction medium selected from the group consisting of xylene, nitrobenzene, trifluorotoluene, 1,2-dichloroethane, acetonitrile, toluene, dimethyl sulfoxide, N,N- Dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, and combinations thereof are carried out in a second solvent.
  • a reaction medium selected from the group consisting of xylene, nitrobenzene, trifluorotoluene, 1,2-dichloroethane, acetonitrile, toluene, dimethyl sulfoxide, N,N- Dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, and combinations thereof are carried out in a second solvent.
  • reaction of step ii) is performed in a second solvent selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide, and combinations thereof.
  • the reaction of step ii) is performed at 100°C to 200°C (e.g., 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C , 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, 185°C, 190°C, 195°C or 200°C) or 100°C-150°C.
  • 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C , 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, 185°C, 190°C, 195°C or 200°C or 100°C-150°C.
  • X is selected from CR2 .
  • X is selected from N.
  • Z is selected from CR4 .
  • Z is selected from N.
  • R 1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, NO 2 , CN, optionally substituted amino, C 1-6 haloalkyl, C 6-12 aryl and C 2-12 heteroaryl.
  • R 1 is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen, NO 2 , CN, optionally substituted amino, C 1-4 haloalkyl, C 6-10 aryl and C 2-10 heteroaryl.
  • R1 is independently selected from hydrogen, alkyl, amino.
  • R1 is independently selected from hydrogen, alkyl.
  • R1 is independently selected from hydrogen, methyl, methoxy, F, Cl, Br, I, NO2 , CN, CF3 , amino.
  • R1 is independently selected from hydrogen, methyl, amino.
  • R1 is independently selected from hydrogen, methyl.
  • R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, amino, NO 2 , CN, C 1-6 haloalkyl, C 6-12 aryl and C 2-12 heteroaryl. In some embodiments, R 2 and R 3 are joined together to form a 3- to 12-membered ring, such as a 5- to 12-membered non-aromatic heterocyclic ring.
  • R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen, amino, NO 2 , CN, C 1-4 haloalkyl, C 6-10 aryl and C 2-10 heteroaryl. In some embodiments, R 2 and R 3 are joined together to form a 5- to 10-membered ring, such as a 5- to 10-membered non-aromatic heterocyclic ring.
  • R2 and R3 are each independently selected from hydrogen, methyl, methoxy, F, Cl, Br, I, amino, NO2 , CN, CF3 .
  • R 2 and R 3 are each independently selected from hydrogen, halogen, and amino.
  • R 2 and R 3 are each independently selected from hydrogen, and halogen.
  • R2 and R3 form a 5- to 7-membered non-aromatic heterocycle, such as 1,3-dioxole.
  • R 4 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, amino, NO 2 , CN, C 1-6 haloalkyl, C 6-12 aryl group and C 2-12 heteroaryl group.
  • R 4 is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen, amino, NO 2 , CN, C 1-4 haloalkyl, C 6-10 aryl group and C 2-10 heteroaryl group.
  • R4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, CN.
  • R4 is independently selected from hydrogen, alkyl, alkoxy, halogen, amino, CN.
  • R4 is independently selected from hydrogen, methyl, methoxy, F, Cl, Br, I, NH2 , NO2 , CN, CF3 .
  • R4 is independently selected from hydrogen, methyl, methoxy, F, Cl, NH2 , CN.
  • R4 is independently selected from hydrogen, methyl, methoxy, F, Cl, CN.
  • R4 is independently selected from halogen or amino.
  • R4 is independently selected from halogen.
  • R5 is independently selected from hydrogen, C 1-6 alkyl optionally substituted by OH or SH, 3-12 membered cycloalkyl optionally substituted by halogen, C 6-12 aryl and C 2-12 heteroaryl.
  • R5 is independently selected from C 1-6 alkyl optionally substituted with OH or SH, 3-12 membered cycloalkyl optionally substituted with halogen, C 6-12 aryl, and C 2-12 heteroaryl.
  • R5 is independently selected from hydrogen, C 1-4 alkyl optionally substituted by OH or SH, 3-8 membered cycloalkyl optionally substituted by halogen, C 6-10 aryl and C 2-10 heteroaryl.
  • R5 is independently selected from hydrogen, alkyl optionally substituted with OH or SH, cycloalkyl optionally substituted with halogen.
  • R5 is independently selected from alkyl optionally substituted with OH or SH, cycloalkyl optionally substituted with halogen.
  • R5 is independently selected from hydrogen, ethyl, cyclopropyl, fluorocyclopropyl, tert-butyl, -( CH2 ) 2OH , -( CH2 ) 2SH , -CH( CH 3 )CH 2 OH, and -CH(CH 3 )CH 2 SH.
  • R5 is independently selected from ethyl, cyclopropyl, fluorocyclopropyl, tert-butyl, -( CH2 ) 2SH , and -CH( CH3 ) CH2OH .
  • R5 is independently selected from ethyl, cyclopropyl, fluorocyclopropyl, and tert-butyl.
  • R6 is independently selected from p-toluenesulfonyl and ethylsulfonyl.
  • the halogen is selected from F, Cl, Br, I.
  • At least one of R2 and R3 is halogen.
  • R3 is halo
  • the compound of Formula I is selected from:
  • the application provides a method for preparing a compound of formula II, which includes the following steps:
  • the compound of formula I is prepared by the method described in the first or second aspect above;
  • the compound of formula I is oxidized to form the compound of formula II,
  • the oxidation is performed in an oxidizing agent selected from the group consisting of potassium permanganate, sodium chlorite/sulfamic acid, potassium persulfate, trichloroisocyanuric acid/TEMPO, manganese dioxide, sodium hypochlorite, hydrogen peroxide , sodium bromate, and combinations thereof in the presence of oxidizing agents.
  • an oxidizing agent selected from the group consisting of potassium permanganate, sodium chlorite/sulfamic acid, potassium persulfate, trichloroisocyanuric acid/TEMPO, manganese dioxide, sodium hypochlorite, hydrogen peroxide , sodium bromate, and combinations thereof in the presence of oxidizing agents.
  • the compound of Formula II is selected from:
  • this application provides a method for preparing a compound of formula III, which includes the following steps:
  • the compound of formula II is prepared by the method described in the third aspect above.
  • the compound of formula II is reacted with an optionally substituted nitrogen-containing heterocyclic compound in the presence of a base to generate the compound of formula III, or the compound of formula II is subjected to Stille coupling reaction to generate the compound of formula III,
  • R 2 and R 3 do not form a ring and R 3 is halogen, preferably R 3 is bromine or chlorine;
  • One or more substituents in the amido group and optionally substituted amino group are optionally substituted N-heterocyclyl, heteroaryl and aryl groups.
  • R 7 is selected from C 1-6 alkyl, C 1-6 alkylamido optionally substituted by C 1-6 alkyl, and C 1-6 alkyl
  • One or more substituents in the radical optionally substituted NH 2 are optionally substituted C 2-12 heteroaryl (eg, pyridyl).
  • the N-heterocyclyl is N-heterocycloalkyl.
  • R is selected from:
  • the compound of Formula III is selected from:
  • the application provides a method for preparing a compound of formula IV, which includes the following steps:
  • the compound of formula II is prepared by the method described in the third aspect above.
  • Z is CR 4 , R 4 is halogen or amino and R 5 is OH or SH substituted alkyl;
  • R4 is fluorine
  • R 5 is OH or SH substituted C 1-6 alkyl.
  • R 5 is OH or SH substituted C 1-4 alkyl.
  • R5 is ethyl or isopropyl, each substituted with OH or SH.
  • R' is C 1-6 alkyl.
  • R' is C 1-4 alkyl.
  • R' is ethyl or isopropyl.
  • the compound of Formula IV is selected from:
  • sodium chlorite/sulfamic acid refers to an oxidizing agent composed of both sodium chlorite and sulfamic acid.
  • the range includes the endpoints thereof and all individual integers and fractions falling within the stated range, and also includes all possible variations of the endpoints and internal integers and fractions therein.
  • Each narrower range formed is combined to form a subgroup of the larger numerical group to the same extent as if each such narrower range were expressly given.
  • the reaction temperature of 80°C-200°C means that the reaction temperature can be, for example, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C °C, 190°C or 200°C, etc. and the range formed by them, etc.
  • Numerical ranges expressing the number of carbon atoms herein refer to each integer within the given range.
  • “C 1 -C 12 " or “C 1-12” means that the group may have 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms.
  • element refers to the number of backbone atoms that make up the ring.
  • 3-12 members means that the number of skeleton atoms constituting the ring is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • halo by itself or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • alkyl include C 1-4 alkyl, C 1-6 alkyl, C 1-8 alkyl, C 1-10 alkyl, C 1-12 alkyl, etc., such as methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, s -butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.; for example, the term "C 1-6 alkyl” refers to a group containing 1 to 6 (e.g.
  • Alkyl groups with 2, 3, 4, 5, 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl base, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkoxy refers to -O-alkyl, where "alkyl” is as defined above, examples of “alkoxy” include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy. "Optionally substituted alkoxy” means that the alkyl group in the group is substituted or unsubstituted.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one double bond composed of carbon atoms and hydrogen atoms, such as C 2-6 alkenyl, C 2-4 alkenyl, etc.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • the term includes cis and trans isomers or mixtures of these isomers.
  • alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms, such as C 2-6 alkynyl, C 2-4 alkynyl, C 2 -3 alkynyl etc.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a fully saturated non-aromatic ring composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cycloalkyl group may be a single ring, condensed polycyclic ring, bridged ring or spiro ring structure.
  • Non-limiting examples of cycloalkyl include, but are not limited to, C 3-18 cycloalkyl, C 3-16 cycloalkyl, C 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-8 cycloalkyl group, C 3-7 cycloalkyl, C 3-6 cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[3.3]heptyl, norbornyl ( Bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pentyl-1-yl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is generally a ring containing from 1 to 5 (eg, 1, 2, 3, 4, 5) heteroatoms independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane.
  • Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl.
  • N-heterocycloalkyl refers to a group having the following structure:
  • Ring A is a heterocycloalkyl ring as defined above containing said nitrogen. That is, a heterocycloalkyl group containing N as the attachment site.
  • heterocyclyl or “heterocycle” refers to a cyclic structure that may be saturated or partially unsaturated, nonaromatic, wherein the cyclic structure contains at least one carbon and at least one carbon selected from Examples of O, N, S heteroatoms (eg 1, 2, 3, 4 or 5 heteroatoms) include heterocycloalkyl, heterocycloalkenyl and heterocycloalkynyl.
  • N-heterocyclyl refers to a group having the following structure:
  • Ring B is a heterocyclyl ring as defined above containing said nitrogen. That is, a heterocyclyl group containing N as the attachment site.
  • the 5- to 12-membered N-heterocyclyl group is a heterocyclic group containing, for example, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms.
  • "Optionally substituted N-heterocyclyl" means that the heterocyclyl portion of the group is substituted or unsubstituted.
  • nitrogen-containing heterocyclic compound refers to a compound containing a heterocyclic ring as defined above containing nitrogen as a ring-forming atom or a compound consisting of a heterocyclic ring as defined above containing nitrogen as a ring-forming atom.
  • cycloalkenyl refers to a non-aromatic mono- or polycyclic ring system containing at least one carbon-carbon double bond.
  • cycloalkenyl rings contain, for example, 3-10 ring atoms, 5-10 ring atoms, or 5-7 ring atoms.
  • suitable monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • a non-limiting example of a suitable polycyclic cycloalkenyl group is norbornenyl.
  • heterocycloalkenyl refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond or carbon-nitrogen double bond and consisting exclusively of carbon and hydrogen atoms, wherein one or more of the ring systems
  • the ring atoms are elements other than carbon.
  • 1, 2, 3, 4, and 5 ring atoms are each independently a heteroatom selected from nitrogen, oxygen, and sulfur. No adjacent oxygen and/or sulfur atoms are present in the ring system.
  • the heterocycloalkenyl ring contains, for example, 5-10 ring atoms, 5-8 ring atoms, 5-7 ring atoms, or, 5-6 ring atoms.
  • aza, oxa or thia before the name of a heterocyclenyl radical indicates that at least one nitrogen, oxygen or sulfur atom is present as a ring atom respectively.
  • suitable monocyclic nitrogen heterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3, 6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 2-pyrazolinyl, etc.
  • Non-limiting examples of suitable oxeterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuryl, fluorodihydrofuryl, and the like.
  • a non-limiting example of a suitable polycyclic oxyheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
  • cycloalkynyl refers to a non-aromatic monocyclic or polycyclic ring having at least one carbon-carbon triple bond and consisting only of carbon and hydrogen atoms, such as 4-15 membered, 5-15 membered, 6-10 membered, 7-membered - a 10- or 8-10-membered ring, such as an 8- to 10-membered monocyclic ring or a 12- to 15-membered bicyclic ring. It may contain one or more fused or bridged rings. Unless otherwise stated, the cycloalkynyl ring can be attached at any carbon atom which results in a stable structure and, if substituted, can be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkynyl groups include cyclooctynyl, cyclononenyl, cyclodecynyl, 2-methylcyclooctynyl, and the like.
  • heterocycloalkynyl means that at least one carbon-carbon single bond in the heterocycloalkyl group is replaced by a carbon-carbon triple bond.
  • aryl refers to an aromatic ring or aromatic or partially aromatic ring system consisting of carbon atoms and hydrogen atoms. It may be a single ring or may be polycyclic rings fused together or covalently connected (eg, two or more rings such as a bicyclic ring).
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • an aryl group can be a monovalent group or a bivalent group, that is, an arylene group.
  • C 6 -C 18 aryl or “aromatic ring” refers to a ring having 6 to 18 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms) aryl group or aromatic ring as defined above.
  • Heteroaryl or “heteroaryl ring” refers to an aromatic ring consisting of carbon atoms and at least one (eg, 1 to 5, such as 1, 2, 3, 4, 5) heteroatom selected from nitrogen, oxygen, and sulfur. ring group.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be any Be oxidized; the nitrogen atoms may be optionally quaternized.
  • Examples include, but are not limited to, azepineyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, Benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) base), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, furyl, thienyl, furanone Base, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, indolinyl, is
  • C 2 -C 12 heteroaryl refers to a group having from 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms)
  • the aromatic ring group also contains at least one heteroatom (for example, 1, 2, 3, 4, 5 heteroatoms) selected from N, O, and S as ring atoms.
  • Carbocyclic ring refers to an aromatic or non-aromatic (partially or fully saturated) carbocyclic ring, such as C3-7 carbocyclic ring, C5-7 carbocyclic ring, C5-12 carbocyclic ring, C5-10 monocyclic ring Carbocyclic rings, etc., examples of which include cycloalkyl, cycloalkenyl, cycloalkynyl and aryl groups, such as: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene , cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, or benzene ring.
  • cycloalkyl such as C3-7 carbocyclic ring, C5-7 carbocyclic
  • cyclic group such as a 3- to 12-membered cyclic group or a 3- to 12-membered ring includes C3-12 carbocyclic rings, 3- to 12-membered heterocyclic rings, and 6- to 12-membered aromatic rings or 5 12-membered heteroaromatic ring.
  • carbocyclic ring, heterocyclic ring, aromatic ring and heteroaromatic ring have the same meanings as above, and examples thereof include: pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazoline, Zolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyrimidine Azine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroaza, perhydroaza, dihydrodiazepine, tetrahydrodiazepine, perhydrodiaza, dihydrofuran, tetrahydrofuran , di
  • optionally substituted amino refers to -NH2 , mono- or di-substituted amino, and 5- to 7-membered cyclic amino groups.
  • an amino group optionally substituted by 1 or more substituents selected from C 1-6 alkyl (eg, methyl).
  • primary amine refers to a compound in which one hydrogen in the ammonia molecule is replaced by a hydrocarbyl group R".
  • R is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted group as defined above. Heteroaryl.
  • R is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted group as defined above. Heteroaryl.
  • R” is alkyl, haloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl. In some embodiments, R” is C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl, C 2 -C 12 heteroaryl, C 1-6 alkyl C 6-12 aryl, C 1-6 alkyl C 2 -C 12 heteroaryl. In some embodiments, R" is alkyl or haloalkyl. In some embodiments, R" is C 1-6 alkyl.
  • acyl refers to a group having the structure -C(O)R", where R" is as defined above. "Optionally substituted acyl” means that the R" portion of the group is substituted or unsubstituted.
  • sulfonyl refers to a group having the structure -SO2R ", where R” is as defined above. "Optionally substituted sulfonyl” means that the R" portion of the group is substituted or unsubstituted.
  • Alkylamido refers to a group having the formula -NHC(O)-Ri, wherein Ri is an alkyl group as defined above.
  • a C 1-7 alkylamido refers to an alkylamido having 1 to 7 carbon atoms (excluding the carbonyl carbon atom).
  • Optionally substituted alkylamino means that the NH part and/or the alkyl part in the alkylamino is optionally substituted. Examples of optionally substituted alkylamino include but are not limited to -N(alkyl)C (O)-Ri.
  • substituents eg, 1 to 4, 1 to 3, or 1 to 2
  • substituents eg, 1 to 4, 1 to 3, or 1 to 2
  • the substituent is One or more groups individually and independently selected from: halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl , Alkoxy, aryloxy, heteroaryloxy, mercapto, alkylthio, arylthio, cyano, carbonyl, thiocarbonyl, alkylamido, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinamido, N-sulfinamido, carboxyl, C-carboxy
  • substituents When a group is substituted with more than one substituent, the substituents may be the same or different, any substituted functional group herein may be substituted at 1 to 4 different positions, and those 1 to 4 substituents can be at 1 Up to 4 positions are replaced independently.
  • the method of the present invention may include the steps of protecting and deprotecting certain groups when necessary.
  • protecting groups such as hydroxyl, thiol and amino protecting groups and protecting groups
  • Principles of group selection and methods of deprotection are well known in the art.
  • This application can realize the one-pot preparation of quinolone compound intermediates without the need to separate intermediate products and directly obtain molecules with complex structures, which is economically and environmentally friendly.
  • the method of the present application has the advantages of short reaction steps, good selectivity and high yield.
  • the yield of the quinolone drug or its intermediate prepared by the method of the present invention is not less than 55%, not less than 60%, Not less than 70%, or not less than 80%, and some can even reach more than 90%; at the same time, the raw materials are cheap and easy to obtain.
  • the precursor compound 15 of ozerofloxacin can be quickly constructed with a yield of 73%.

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Abstract

提供了一种喹诺酮类化合物及其中间体的制备方法，特别是喹诺酮和喹啉酮医药中间体的制备方法，具体地，提供了式Ⅰ化合物的制备方法以及以式Ⅰ化合物作为中间体合成喹诺酮类化合物的方法，式Ⅰ化合物的制备方法包括如下步骤：将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式Ⅰ化合物。

Description

喹诺酮类化合物及其中间体的制备方法
相关申请的交叉引用
本申请要求于2022年4月18日向中国国家知识产权局提交的第202210437152.2号中国发明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本文中。
技术领域
本申请涉及药物化学领域。具体而言，本申请涉及喹诺酮类化合物及其中间体(例如喹啉酮类化合物)的制备方法，特别是喹诺酮和喹啉酮医药中间体的制备方法。
背景技术
喹诺酮类化合物作为药物骨架，在临床上广泛用于抗菌、抗癌和囊性纤维化等的治疗，具有抗菌谱广、药用活性强、毒性低及疗效高等诸多优点。
目前喹诺酮类药物的合成主要有以下三种方法：
(a)苯胺类衍生物与乙氧亚甲基丙二酸二乙酯缩合；在聚磷酸乙酯或聚磷酸条件下，发生胺基邻位官能化，发生环化反应，即得关键中间体；通过烷基化反应，将喹啉氮原子官能化，得到含有取代基的喹啉酮类化合物；最后经过水解和酸化等步骤得到喹诺酮类化合物。方法(a)需要使用较昂贵的EMME反应原料，并且在第二步PPA和POCl 3环合过程中，反应的选择性不高，导致产率较低。
(b)苯甲酰乙酸乙酯为起始原料，首先和原甲酸三乙酯反应，与脂肪胺缩合生成化合物烯胺二羰基化合物。经过碱性条件下，发生分子内亲核取代反应，获得环合中间体，最后在HCl条件下水解，得到喹诺酮中间体。方法(b)中2-氟苯甲酰乙酸乙酯原料的价格昂贵，同时缩醛试剂：原甲酸三乙酯是激性气味的液体，熔沸点不高，不易储存。
(c)以邻氟苯甲酸类化合物为原料，经酰氯化后，酰氯与N,N-二甲氨基丙烯酸乙酯偶联，形成烯胺类中间体，再通过胺与烯胺二羰基类化合物发生胺的置换反应。在碱性条件下，发生分子内环合，获得喹诺酮药物前体，经过水解得到目标产物。虽然方法(c)中邻氟苯甲酸原料易得，但是需要5步才能获得喹诺酮药物前体，操作复杂。
Figure PCTCN2022090989-appb-000001
快速、简单、高效地构建喹诺酮类药物分子，以满足患者需求，具有十分重要的实际意义。
发明内容
在第一方面，本申请提供了式I化合物的制备方法，其包括如下步骤：
将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式I化合物，
Figure PCTCN2022090989-appb-000002
其中：
X选自CR 2或N；
Z选自CR 4或N；
R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
R 6独立地选自磺酰基。
在第二方面，本申请提供了式I化合物的制备方法，其包括如下步骤：
i)将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式B化合物，以及
ii)将式B化合物在碱的存在下反应生成式I化合物，
其中步骤ii)的所述反应在高于步骤i)的反应温度的温度下进行；
Figure PCTCN2022090989-appb-000003
其中：
X选自CR 2或N；
Z选自CR 4或N；
R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
R 6独立地选自磺酰基。
在第三方面，本申请提供了式II化合物的制备方法，其包括如下步骤：
通过上述第一方面或第二方面所述的方法制得式I化合物；以及
使式I化合物氧化生成式II化合物，
Figure PCTCN2022090989-appb-000004
其中，式II中的X、Z、R 1、R 2、R 3、R 4和R 5的定义与式I中所定义的相同。
在第四方面，本申请提供了式III化合物的制备方法，其包括如下步骤：
通过上述第三方面所述的方法制得式II化合物；以及
使式II化合物与任选取代的含氮杂环化合物在碱的存在下反应生成式III化合物,或者使式II化合物发生Stille偶联反应生成式III化合物,
Figure PCTCN2022090989-appb-000005
其中：
在式II中，R 2和R 3不形成环并且R 3为卤素；
在式III中，X、Z、R 1、R 2、R 4和R 5的定义与式II中所定义的相同，并且R 7选自任选取代的N-杂环基、任选取代的杂芳基和任选取代的芳基。
在第五方面，本申请提供了式IV化合物的制备方法，其包括如下步骤：
通过上述第三方面所述的方法制得式II化合物；以及
使式II化合物在合适的条件下反应生成式IV化合物,
Figure PCTCN2022090989-appb-000006
其中在式II中，Z为CR 4，R 4为卤素或氨基并且R 5为OH或SH取代的烷基；
其中在式IV中，X、R 1、R 2和R 3的定义与式II中所定义的相同，并且Y为O或S，R'为烷基。
具体实施方式
在第一方面，本申请提供了式I化合物的制备方法，其包括如下步骤：
将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式I化合物，
Figure PCTCN2022090989-appb-000007
其中：
X选自CR 2或N；
Z选自CR 4或N；
R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
R 6独立地选自磺酰基。
在一些实施方案中，所述碱选自无机碱、有机碱、及其组合。
在一些实施方案中，所述碱选自一级胺。
在一些实施方案中，所述碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、三乙胺、二异丙基胺、二氮杂二环(DBU)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、及其组合。
在一些实施方案中，所述碱选自碳酸钾、碳酸铯、碳酸钠、及其组合。
在一些实施方案中，所述反应在溶剂中进行。
在一些实施方案中，所述反应在选自甲醇、乙醇、乙腈、甲苯、水、N,N-二甲基甲酰胺、二甲苯、硝基苯、三氟甲苯、N-甲基吡咯烷酮、1,2-二氯乙烷、1,4-二氧六环、及其组合的溶剂中进行。
在一些实施方案中，所述反应在选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、及其组合的溶剂中进行。
在一些实施方案中，所述反应在80℃-200℃(例如80℃、90℃、100℃、110℃、120℃、130℃、140℃、150℃、160℃、170℃、180℃、190℃或200℃)或100℃-150℃的温度下进行。
在第二方面，本申请提供了式I化合物的制备方法，其包括如下步骤：
i)将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式B化合物，以及
ii)将式B化合物在碱的存在下反应生成式I化合物，
其中步骤ii)的所述反应在高于步骤i)的反应温度的温度下进行；
Figure PCTCN2022090989-appb-000008
其中：
X选自CR 2或N；
Z选自CR 4或N；
R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
R 6独立地选自磺酰基。
在一些实施方案中，所述步骤i)中的碱选自无机碱、有机碱及其组合。在一些实施方案中，所述步骤i)中的碱选自一级胺，优选过量的一级胺。
在一些实施方案中，所述步骤i)中的碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、三乙胺、二异丙基胺、二氮杂二环、1,4-二氮杂二环[2.2.2]辛烷、及其组合。
所述步骤i)中的碱选自叔丁醇锂、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、三乙胺、二异丙基胺、二氮杂二环、及其组合。
在一些实施方案中，步骤i)的所述反应在第一溶剂中进行。
在一些实施方案中，步骤i)的所述反应在选自甲醇、乙醇、乙腈、甲苯、水、二甲基亚砜、N,N-二甲基甲酰胺、1,4-二氧六环及其组合的第一溶剂中进行。
在一些实施方案中，步骤i)的所述反应在室温至150℃(例如20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃、125℃、130℃、135℃、140℃、145℃或150℃)或室温至100℃的温度下进行。
在一些实施方案中，所述步骤ii)中的碱选自无机碱。
在一些实施方案中，所述步骤ii)中的碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、及其组合。
在一些实施方案中，所述步骤ii)中的碱选自碳酸钾、碳酸铯、碳酸钠、及其组合。
在一些实施方案中，步骤ii)的所述反应在第二溶剂中进行，其中所述第二溶剂与所述第一溶剂可以相同或不同。
在一些实施方案中，步骤ii)的所述反应在选自二甲苯、硝基苯、三氟甲苯、1,2-二氯乙烷、乙腈、甲苯、二甲基亚砜、N,N-二甲基甲酰胺、1,4-二氧六环、N-甲基吡咯烷酮、及其组合的第二溶剂中进行。
在一些实施方案中，步骤ii)的所述反应在选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、及其组合的第二溶剂中进行。
在一些实施方案中，步骤ii)的所述反应在100℃-200℃(例如100℃、105℃、110℃、115℃、120℃、125℃、130℃、135℃、140℃、145℃、150℃、155℃、160℃、165℃、170℃、175℃、180℃、185℃、190℃、195℃或200℃)或100℃-150℃的温度下进行。
在一些实施方案中，X选自CR 2。
在一些实施方案中，X选自N。
在一些实施方案中，Z选自CR 4。
在一些实施方案中，Z选自N。
在一些实施方案中，R 1独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、NO 2、CN、任选取代的氨基、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基。
在一些实施方案中，R 1独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、NO 2、CN、任选取代的氨基、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基。
在一些实施方案中，R 1独立地选自氢、烷基、氨基。
在一些实施方案中，R 1独立地选自氢、烷基。
在一些实施方案中，R 1独立地选自氢、甲基、甲氧基、F、Cl、Br、I、NO 2、CN、CF 3、氨基。
在一些实施方案中，R 1独立地选自氢、甲基、氨基。
在一些实施方案中，R 1独立地选自氢、甲基。
在一些实施方案中，R 2和R 3各自独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、氨基、NO 2、CN、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基。在一些实施方案中，R 2与R 3连接在一起以形成3元-12元环，例如5元-12元非芳香族杂环。
在一些实施方案中，R 2和R 3各自独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、氨基、NO 2、CN、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基。在一些实施方案中，R 2与R 3连接在一起以形成5元-10元环，例如5元-10元非芳香族杂环。
在一些实施方案中，R 2和R 3各自独立地选自氢、甲基、甲氧基、F、Cl、Br、I、氨基、NO 2、CN、CF 3。
在一些实施方案中，R 2和R 3各自独立地选自氢、卤素、和氨基。
在一些实施方案中，R 2和R 3各自独立地选自氢、和卤素。
在一些实施方案中，R 2和R 3形成5元-7元非芳香族杂环，例如1,3-二氧杂环戊烯。
在一些实施方案中，R 4独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、氨基、NO 2、CN、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基。
在一些实施方案中，R 4独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、氨基、NO 2、CN、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基。
在一些实施方案中，R 4独立地选自氢、烷基、烷氧基、卤素、氨基、CN。
在一些实施方案中，R 4独立地选自氢、烷基、烷氧基、卤素、氨基、CN。
在一些实施方案中，R 4独立地选自氢、甲基、甲氧基、F、Cl、Br、I、NH 2、NO 2、CN、CF 3。
在一些实施方案中，R 4独立地选自氢、甲基、甲氧基、F、Cl、NH 2、CN。
在一些实施方案中，R 4独立地选自氢、甲基、甲氧基、F、Cl、CN。
在一些实施方案中，R 4独立地选自卤素或氨基。
在一些实施方案中，R 4独立地选自卤素。
在一些实施方案中，R 5独立地选自氢、被OH或SH任选取代的C 1-6烷基、被卤素任选取代的3元-12元环烷基、C 6-12芳基和C 2-12杂芳基。
在一些实施方案中，R 5独立地选自被OH或SH任选取代的C 1-6烷基、被卤素任选取代的3元-12元环烷基、C 6-12芳基和C 2-12杂芳基。
在一些实施方案中，R 5独立地选自氢、被OH或SH任选取代的C 1-4烷基、被卤素任选取代的3元-8元环烷基、C 6-10芳基和C 2-10杂芳基。
在一些实施方案中，R 5独立地选自氢、被OH或SH任选取代的烷基、被卤素任选取代的环烷基。
在一些实施方案中，R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基。
在一些实施方案中，R 5独立地选自氢、乙基、环丙烷基、氟代环丙烷基、叔丁基、-(CH 2) 2OH、-(CH 2) 2SH、-CH(CH 3)CH 2OH、和-CH(CH 3)CH 2SH。
在一些实施方案中，R 5独立地选自乙基、环丙烷基、氟代环丙烷基、叔丁基、-(CH 2) 2SH、和-CH(CH 3)CH 2OH。
在一些实施方案中，R 5独立地选自乙基、环丙烷基、氟代环丙烷基、和叔丁基。
在一些实施方案中，R 6独立地选自对甲苯磺酰基和乙基磺酰基。
在一些实施方案中，所述卤素选自F、Cl、Br、I。
在一些实施方案中，R 2和R 3中至少之一为卤素。
在一些实施方案中，R 3为卤素。
在一些实施方案中，所述式I化合物选自：
Figure PCTCN2022090989-appb-000009
在第三方面，本申请提供了式II化合物的制备方法，其包括如下步骤：
通过上述第一方面或第二方面所述的方法制得式I化合物；以及
使式I化合物氧化生成式II化合物，
Figure PCTCN2022090989-appb-000010
其中，式II中的X、Z、R 1、R 2、R 3、R 4和R 5的定义与式I中所定义的相同。
在一些实施方案中，所述氧化在选自高锰酸钾、亚氯酸钠/氨基磺酸、过硫酸氢钾的氧化剂、三氯异氰尿酸/TEMPO、二氧化锰、次氯酸钠、过氧化氢、溴酸钠、及其组合的氧化剂的存在下进行。
在一些实施方案中，所述式II化合物选自：
Figure PCTCN2022090989-appb-000011
第四方面，本申请提供了式III化合物的制备方法，其包括如下步骤：
通过上述第三方面所述的方法制得式II化合物；以及
使式II化合物与任选取代的含氮杂环化合物在碱的存在下反应生成式III化合物,或者使式II化合物发生Stille偶联反应生成式III化合物,
Figure PCTCN2022090989-appb-000012
其中：
在式II中，R 2和R 3不形成环并且R 3为卤素，优选地R 3为溴或氯；
在式III中，X、Z、R 1、R 2、R 4和R 5的定义与式II中所定义的相同，并且R 7选自任选取代的N-杂环基、任选取代的杂芳基和任选取代的芳基。本领域技术人员可以理解，使式II化合物与任选取代的含氮杂环化合物在碱的存在下反应可以生成其中R 7选自任选取代的N-杂环基的式III化合物。当希望制备的是其中R 7选自任选取代的杂芳基或任选取代的芳基的式III化合物时，可以通过使式II化合物发生Stille偶联反应生成其中R 7选自任选取代的杂芳基或任选取代的芳基的式III化合物。
在一些实施方案中，所述任选取代的含氮杂环化合物选自：被选自任选被NH 2取代的烷基、＝N(烷氧基)、烷氧基、环烷基、羟基、和任选取代的氨基中的一个或多个取代基任选取代的含氮杂环化合物。
在一些实施方案中，所述任选取代的含氮杂环化合物选自：各自被选自任选被NH 2 取代的C 1-6烷基、＝N(C 1-6烷氧基)、C 1-6烷氧基、3元-7元环烷基、羟基、和NH 2中的一个或多个取代基任选取代的哌啶、哌嗪、四氢吡咯、吡咯并吗啉、吡咯并哌啶、氮杂螺[2.4]庚烷和氮杂环庚烷；其中所述NH 2任选被一个或多个选自C 1-6烷基的基团取代。
在一些实施方案中，R 7选自各自被选自任选被NH 2取代的烷基、＝N(烷氧基)、烷氧基、环烷基、羟基、任选被烷基取代的烷基酰氨基和任选取代的氨基中的一个或多个取代基任选取代的N-杂环基、杂芳基和芳基。
在一些实施方案中，R 7选自各自被选自任选被NH 2取代的C 1-6烷基、＝N(C 1-6烷氧基)、C 1-6烷氧基、3元-7元环烷基、羟基、任选被C 1-6烷基取代的C 1-6烷基酰氨基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的5元-12元N-杂环基、C 2-12杂芳基和C 6-12芳基。
在一些实施方案中，R 7选自被选自任选被NH 2取代的C 1-6烷基、＝N(C 1-6烷氧基)、3元-7元环烷基、羟基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的5元-12元N-杂环基。
在一些实施方案中，R 7选自被选自C 1-6烷基、任选被C 1-6烷基取代的C 1-6烷基酰氨基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的C 2-12杂芳基(例如吡啶基)。
在一些实施方案中，所述N-杂环基为N-杂环烷基。
在一些实施方案中，R 7选自：
Figure PCTCN2022090989-appb-000013
在一些实施方案中，所述式III化合物选自：
Figure PCTCN2022090989-appb-000014
在第五方面，本申请提供了式IV化合物的制备方法，其包括如下步骤：
通过上述第三方面所述的方法制得式II化合物；以及
使式II化合物在亲核取代反应条件下反应生成式IV化合物,
Figure PCTCN2022090989-appb-000015
其中在式II中，Z为CR 4，R 4为卤素或氨基并且R 5为OH或SH取代的烷基；
其中在式IV中，X、R 1、R 2和R 3的定义与式II中所定义的相同，并且Y为O或S，R'为 烷基。
在一些实施方案中，R 4为氟。
在一些实施方案中，R 5为OH或SH取代的C 1-6烷基。
在一些实施方案中，R 5为OH或SH取代的C 1-4烷基。
在一些实施方案中，R 5为各自被OH或SH取代的乙基或异丙基。
在一些实施方案中，R'为C 1-6烷基。
在一些实施方案中，R'为C 1-4烷基。
在一些实施方案中，R'为乙基或异丙基。
在一些实施方案中，所述式IV化合物选自：
Figure PCTCN2022090989-appb-000016
在不冲突的情况下，应理解上述实施方案可以组合，形成包括所组合的实施方案的特征的技术方案。这样的组合的技术方案在本发明的范围内。
定义
提供以下定义和方法用以更好地界定本申请以及在本申请实践中指导本领域普通技术人员。除非另作说明，术语按照相关领域普通技术人员的常规用法理解。
词语“包括/包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
氧化剂“亚氯酸钠/氨基磺酸”是指由亚氯酸钠和氨基磺酸两者组成的氧化剂。
凡在本文中给出某一数值范围之处，所述范围包括其端点，以及位于所述范围内的所有单独整数和分数，并且还包括由其中那些端点和内部整数和分数的所有各种可能组合形成的每一个较窄范围，以在相同程度的所述范围内形成更大数值群的子群，如同每一个那些较窄范围被明确给出一样。例如，反应温度为80℃-200℃是指所述反应温度可以为例如80℃、90℃、100℃、110℃、120℃、130℃、140℃、150℃、160℃、170℃、180℃、190℃或200℃等以及由它们所形成的范围等。
本文中表示碳原子数的数字范围，是指给定范围中的各个整数，例如，“C 1-C 12”或“C 1-12”是指该基团可具有1、2、3、4、5、6、7、8、9、10、11、12个碳原子。
术语“元”是表示构成环的骨架原子的个数。例如“3元-12元”是表示构成环的骨架原子的个数为3、4、5、6、7、8、9、10、11或12个。
术语“卤”、“卤代”或“卤素”本身或作为另一取代基的一部分表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
术语“烷基”是指直链或支链的饱和烃基，烷基的实例包括C 1-4烷基、C 1-6烷基、C 1-8烷基、C 1-10烷基、C 1-12烷基等，例如甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等；例如，术语“C 1-6烷基”指含有1至6(例如1、2、3、4、5、6)个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。
术语“烷氧基”是指-O-烷基，其中“烷基”定义如上，“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基。“任选取代的烷氧基”是指该基团中的烷基被取代或未取代。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基，如C 2-6烯基、C 2-4烯基等。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。该术语包括顺式和反式异构体或这些异构体的混合物。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基，如C 2-6炔基、C 2-4炔基、C 2-3炔基等。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。
术语“环烷基”是指由碳原子和氢原子组成的完全饱和的非芳香性环，优选包含1或2个环。所述环烷基可以是单环、稠合多环、桥环或螺环结构。环烷基的非限制性实例包括但不限于C 3-18环烷基、C 3-16环烷基、C 3-12环烷基、C 3-10环烷基、C 3-8环烷基、C 3-7环烷基、C 3-6环烷基等，例如环丙基、环丁基、环戊基、环己基、环庚基、螺[3.3]庚基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至5个(如1、2、3、4、5个)独立地选自硫、氧和/或氮的杂原子的环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。
术语“N-杂环烷基”是指具有下述结构的基团：
Figure PCTCN2022090989-appb-000017
其中环A为包含所述氮的如上所定义的杂环烷基环。即，包含N作为连接位点的杂环烷基。
除非另有指明，术语“杂环基”或“杂环”是指可为饱和或部分不饱和的、非芳香性的环状结构，其中所述环状结构含有至少一个碳和至少一个选自O、N、S的杂原子(例如1、2、3、4或5个杂原子)，其实例包括杂环烷基、杂环烯基和杂环炔基。
术语“N-杂环基”是指具有下述结构的基团：
Figure PCTCN2022090989-appb-000018
其中环B为包含所述氮的如上所定义的杂环基环。即，包含N作为连接位点的杂环基。5元-12元N-杂环基是含有例如5、6、7、8、9、10、11、12个成环原子的杂环基。“任选取代的N-杂环基”是指该基团中的杂环基部分被取代或未取代。
术语“含氮杂环化合物”是指包含含有氮作为成环原子的如上定义的杂环的化合物或由含有氮作为成环原子的如上定义的杂环构成的化合物。
术语“环烯基”是指含有至少一个碳-碳双键的非芳香单-或多环环系。在一些实施方案中，环烯基环含有例如3-10个环原子、5-10个环原子，或5-7个环原子。合适单环环烯基的非限制实例包括环戊烯基、环己烯基、环庚烯基等。合适多环环烯基的非限制实例是降莰烯基。
术语“杂环烯基”是指含有至少一个碳-碳双键或碳-氮双键并且仅仅由碳和氢原子组成的非芳香单环或多环环系，其中环系中的一个或多个环原子是除碳以外的元素，例如1、2、3、4、5个环原子各自独立地为选自氮、氧、和硫的杂原子。在环系中不存在相邻氧和/或硫原子，在一些实施方案中，杂环烯基环含有例如5-10个环原子，5-8个环原子、5-7个环原子或、5-6个环原子。在杂环烯基根名称前的前辍氮杂、氧杂或硫杂表示至少一个氮、氧或硫原子分别作为环原子存在。合适的单环氮杂环烯基的非限制实例包括1，2，3，4-四氢吡啶、1，2-二氢吡啶基、1，4-二氢吡啶基、1，2，3，6-四氢吡啶、1，4，5，6-四氢嘧啶、2-吡咯烷基、3-吡咯烷基、2-咪唑啉基、2-吡唑啉基等。合适氧杂环烯基的非限制实例包括3，4-二氢-2H-吡喃、二氢呋喃基、氟二氢呋喃基等。合适多环氧杂环烯基的非限制实例是7-氧杂双环[2.2.1]庚烯基。
术语“环炔基”是指具有至少一个碳-碳三键并且仅仅由碳和氢原子组成的非芳香单环或多环，例如4-15元、5-15元、6-10元、7-10元或8-10元环，诸如8-至10-元单环或12-至15-元双环。其可以包含一个或多个稠合或桥连的环。除非另有说明，环炔基环可以在任何碳原子处被连接，其产生一种稳定结构，并且，如果被取代的话，可以在任何合适的碳原子处被取代，其产生一种稳定结构。示例性的环炔基基团包括环辛炔基、环壬炔基、环癸炔基、2-甲基环辛炔基等等。
术语“杂环炔基”是指杂环烷基中至少某一个碳碳单键被一个碳碳三键所取代。
术语“芳基”或“芳环”是指由碳原子和氢原子组成的芳环或芳族的或部分芳族的环系统。其可为单环或可为稠合在一起或共价连接的多环(如双环等2个以上的环)。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。根据结构，芳基可以是单价基团或双价基团，即亚芳基。
术语“C 6-C 18芳基”或“芳环”是指具有6至18个碳原子(例如6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子)的如上所定义的芳基或芳环。
“杂芳基”或“杂芳环”指由碳原子和至少一个(例如1至5个，如1、2、3、4、5个)选自氮、氧和硫的杂原子组成的芳环基团。杂芳基基团可以是单环、双环、三环或四环环体系，其可以包含稠合的或桥联的环体系；并且杂芳基基团中的氮、碳或硫原子可以任意地被氧化；氮原子可以任意地季铵化。实例包括但不限于氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并噻二唑基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基、苯并二噁英基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并苯硫基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、呋喃基、噻吩基、呋喃酮基、异噻唑基、咪唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、中氮茚基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙烷基、吩嗪基、吩噻嗪基、吩噁嗪基、2,3-二氮杂萘基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基以及苯硫基。
术语“C 2-C 12杂芳基”是指具有除了2个至12个碳原子(例如2、3、4、5、6、7、8、9、10、11、或12个碳原子)之外还含有作为成环原子的选自N、O、和S中的至少一个杂原子(例如1、2、3、4、5个杂原子)的芳环基团。
术语“碳环”是指芳香性的或非芳香性的(部分饱和或全部饱和)的碳环，例如C3-7碳环、C5-7碳环、C5-12碳环、C5-10单环碳环等，其实例包括环烷基、环烯基、环炔基和芳基，例如：环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环丁烯、环戊烯、环己烯、环庚烯、环丁二烯、环戊二烯、环己二烯、环庚二烯、或苯环。
术语“环基团”或“环”例如3元-12元环基团或3元-12元环包括C3-12碳环、3元-12元杂环和6元-12元芳环或5元-12元杂芳环。这里，碳环、杂环、芳环和杂芳环具有与上面相同的含义，其实例包括：吡咯啉、吡咯烷、咪唑啉、咪唑烷、三唑啉、三唑烷、四唑啉、四唑烷、吡唑啉、吡唑烷、二氢吡啶、四氢吡啶、哌啶、二氢吡嗪、四氢吡嗪、哌嗪、二氢嘧啶、四氢嘧啶、全氢嘧啶、二氢哒嗪、四氢哒嗪、全氢哒嗪、二氢氮杂、四氢氮杂、全氢氮杂、二氢二氮杂、四氢二氮杂、全氢二氮杂、二氢呋喃、四氢呋喃、二氢吡喃、四氢吡喃、二氢氧杂、四氢氧杂、全氢氧杂、二氢噻吩、四氢噻吩、二氢噻喃、 四氢噻喃、二氢硫杂、四氢硫杂、全氢硫杂、二氢唑、四氢唑(唑烷)、二氢异唑、四氢异唑(异唑烷)、二氢噻唑、四氢噻唑(噻唑烷)、二氢异噻唑、四氢异噻唑(异噻唑烷)、二氢呋咱、四氢呋咱、二氢二唑、四氢二唑(二唑烷)、二氢嗪、四氢嗪、二氢二嗪、四氢二嗪、二氢氧氮杂、四氢氧氮杂、全氢氧氮杂、二氢氧杂二氮、四氢氧杂二氮、全氢氧杂二氮、二氢噻二唑、四氢噻二唑(噻二唑烷)、二氢噻嗪、四氢噻嗪、二氢噻二嗪、四氢噻二嗪、二氢硫氮杂、四氢硫氮杂、全氢硫氮杂、二氢硫杂二氮杂、四氢硫杂二氮杂、全氢硫杂二氮杂、吗啉、硫代吗啉、噻嗪、二氧戊环、二烷、二硫戊环、二噻烷、吡咯、咪唑、三唑、四唑、吡唑、吡啶、哌嗪、嘧啶、哒嗪、氮杂、二氮杂、呋喃、吡喃、氧杂、噻吩、噻喃、硫杂、唑、异唑、噻唑、异噻唑、呋咱、二唑、嗪、二嗪、噻二唑、噻嗪、噻二嗪、硫氮杂或硫二氮杂环。
在本说明书中，
Figure PCTCN2022090989-appb-000019
意指连接位置。
术语“任选取代的氨基”是指-NH 2，单-或二-取代氨基，以及5-至7-元环状氨基。例如被1个或多个选自C 1-6烷基(例如甲基)的取代基任选取代的氨基。
术语“一级胺”是指氨分子中的一个氢被烃基R”取代而生成的化合物。其中R”为如上所定义的任选取代的烷基、任选取代的芳基或任选取代的杂芳基。在一些实施方案中，
R”为烷基、卤代烷基、芳基、杂芳基、烷基芳基、烷基杂芳基。在一些实施方案中，R”为C 1-6烷基、C 1-6卤代烷基、C 6-12芳基、C 2-C 12杂芳基、C 1-6烷基C 6-12芳基、C 1-6烷基C 2-C 12杂芳基。在一些实施方案中，R”为烷基或卤代烷基。在一些实施方案中，R”为C 1-6烷基。
本文中所用的术语“酰基”是指具有-C(O)R”结构的基团，其中R”如上所定义。“任选取代的酰基”是指该基团中的R”部分被取代或未取代。
本文中所用的术语“磺酰基”是指具有-SO 2R”结构的基团，其中R”如上所定义。“任选取代的磺酰基”是指该基团中的R”部分被取代或未取代。
本文中所用的“烷基酰氨基”指具有式-NHC(O)-Ri的基团，其中Ri为如上文所定义的烷基。例如，C 1-7烷基酰氨基指具有1-7个碳原子(不包括羰基碳原子)的烷基酰氨基。任选取代的烷基酰氨基是指烷基酰氨基中的NH部分和/或烷基部分被任选取代,任选取代的烷基酰氨基的实例包括但不限于-N(烷基)C(O)-Ri。
术语“任选取代的”是指基团未被取代或者被一个或多个取代基(例如1至4个、1至3个或1至2个)取代，当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：卤素、羟基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、芳基、杂芳基、杂环基、烷氧基、芳氧基、杂芳氧基、巯基、烷硫基、芳硫基、氰基、羰基、硫代羰基、烷基酰氨基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、羧基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、酯基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物等。并且这些列举的取代基团还可以进一步被烷基或卤素任选取代。每当取代基被描述为被“任意取代的”时，取代基可被上 述取代基之一取代。
当基团被多于一个的取代基取代时，取代基可以相同或不同，本文中任何取代的官能团可以在1至4个不同的位置被取代，并且那些1至4个取代基团能够在1至4个位置各自独立地被取代。
本领域技术人员知晓，本发明的方法在有必要的时候可以包括对某些基团进行保护和脱保护的步骤，常用的保护基团例如羟基、硫醇基、氨基的保护基团和保护基团的选择原则和脱保护的方法在本领域中是众所周知的。
本申请的各项发明提供了以下优势：
本申请可以实现一锅法制备喹诺酮类化合物中间体，无需分离中间产物，直接获得结构复杂的分子，在经济上和环境友好上较为有利。
此外，本申请的方法具有反应步骤短，选择性好，产率高的优点，通过本发明的方法制得的喹诺酮药物或其中间体的产率不低于55％、不低于60％、不低于70％、或不低于80％、有的甚至能达到90％以上；同时原料廉价易得。
实施例
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例仅用于说明的目的，而非用来限制本申请的范围。
实施例1
环丙沙星及格雷沙星类似物合成：
Figure PCTCN2022090989-appb-000020
具体合成环丙沙星的步骤如下：
在25mL的圆底烧瓶中，先将6，7-二氟-3-甲酰基色酮(0.5mmol)，环丙胺(1.2mmol)，对甲苯磺酰氯(0.5mmol)置于水(5.0mL)中。在100℃下5小时后，通过薄层色谱检测，如果没有6,7-二氟-3-甲酰基色酮和对甲苯磺酰氯剩余，表明反应完全。待反应液冷却至室温，向反应液中加入乙酸乙酯，每次15.0mL，萃取三次。有机相使用无水硫酸钠干燥后，采用柱层析进行分离，得到目标化合物1，产率67％。 1H NMR(400MHz,CDCl 3)δ11.16–10.86(m,1H),9.05(d,J＝1.5Hz,1H),8.07(s,1H),7.63(dt,J＝8.4,1.7Hz,2H),7.23(ddd,J＝9.8,8.4,1.5Hz,1H),7.18–7.07(m,1H),3.00(ddq,J＝32.7,7.6,3.7Hz,1H),2.46(s,3H),1.05–0.91(m,2H),0.92–0.79(m,2H). 13C NMR(101MHz,CDCl 3)δ190.54,189.16,187.40,186.74,160.57,151.98,149.44,147.71,147.58,146.22,146.05,141.48,141.39, 131.78,131.67,130.42,129.98,129.94,128.53,118.34,118.15,117.95,117.76,113.43,113.29,113.23,113.08,110.39,77.35,77.24,77.04,76.72,31.14,30.99,21.82,21.81,6.70,6.61.HRMS(ESI)计算值：C 20H 18F 2NO 5S[M+H] +422.0868，实测值:422.0871。
将化合物1(0.2mmol)溶于二甲基亚砜(DMSO)中，然后再向体系中加入氢氧化钠(0.4mmol)。将反应体系升温至120℃，反应6小时。通过薄层色谱检测，如果没有原料剩余，将反应液冷却至室温，向反应液中加入乙酸乙酯，每次15mL，萃取三次。有机相使用无水硫酸钠干燥后，采用柱层析进行分离，得到目标化合物2，产率89％。 1H NMR(400MHz,CDCl 3)δ10.36(s,1H),8.43(s,1H),8.27(dd,J＝10.1,8.6Hz,1H),7.80(dd,J＝11.2,6.3Hz,1H),3.49(t,J＝3.7Hz,1H),1.40(d,J＝6.8Hz,2H),1.25–1.14(m,2H). 13C NMR(101MHz,CDCl 3)δ188.94,175.36,154.95,154.81,152.40,152.25,150.25,150.12,147.74,147.60,145.93,138.16,138.06,126.17,126.12,126.09,116.79,115.09,115.07,114.91,114.88,106.35,106.13,99.98,77.35,77.24,77.04,76.86,76.72,76.54,35.12,8.24.HRMS(ESI)计算值C 13H 10F 2NO 2[M+H] +250.0674,实测值:250.0679。
将化合物2(0.2mmol)溶于1,4-二氧六环和水溶液(3mL,2:1)中，称量氢氧化钠和高锰酸钾各(0.4mmol)加入反应液中。反应在室温下搅拌7小时后，通过薄层色谱检测。如果没有原料剩余，蒸干溶剂，采用柱层析进行分离，得到目标化合物3，产率57％。将化合物3(0.2mmol)，哌嗪(0.22mmol)和三乙胺(0.22mmol)溶于5mL DMSO中。在微波条件下，将反应体系温度升高至微波150℃，搅拌0.5h，通过薄层色谱检测，如果没有原料剩余，将反应液冷却至室温。最后用甲醇重结晶，获得环丙沙星4，产率63％。 1H NMR(400MHz,D 2O)δ8.29(s,1H),7.23(d,J＝7.1Hz,1H),7.02(d,J＝12.9Hz,1H),3.42(d,J＝33.8Hz,8H),1.28(d,J＝6.5Hz,2H),1.00(s,2H). 13C NMR(101MHz,D 2O)δ175.28,168.41,154.31,151.81,147.84,144.50,144.40,138.62,118.20,118.12,110.39,110.16,106.25,105.24,46.18,46.13,43.09,36.02,7.40.HRMS(ESI)计算值C 17H 19FN 3O 3[M+H] +322.1405,实测值:322.1410。
另外，将该步反应中的哌嗪换成2-甲基哌嗪，在相同的条件下，可以分离得到格雷沙星类似物5，产率72％。 1H NMR(400MHz,DMSO-d 6)δ8.64(s,1H),7.87(d,J＝13.3Hz,1H),7.53(d,J＝7.4Hz,1H),3.90–3.79(m,1H),3.58(s,2H),3.36(s,2H),3.08(s,2H),2.98(d,J＝8.7Hz,2H),2.69(s,1H),1.31(d,J＝6.8Hz,2H),1.22–1.15(m,2H),1.11(d,J＝6.3Hz,3H). 13C NMR(101MHz,DMSO)δ176.76,176.73,166.39,154.62,152.15,148.37,145.65,145.55,139.65,118.94,118.86,111.51,111.28,107.14,106.72,106.68,56.22,50.48,49.43,44.90,36.32,18.85,8.04,8.01.HRMS(ESI)计算值C 18H 20FN 3O 3[M+H] +346.1562,实测值:346.1569。
实施例2
诺氟沙星和培氟沙星的合成：
Figure PCTCN2022090989-appb-000021
具体合成诺氟沙星的步骤如下：
在25mL的圆底烧瓶中，先将6，7-二氟-3-甲酰基色酮(0.5mmol)，乙胺(0.5mmol)，对甲苯磺酰氯(0.5mmol)置于乙腈(5.0mL)中，随后称取碳酸钾(0.6mmol)加入反应体系中。加料完成后，将反应体系升高温度至60℃，5小时后，通过薄层色谱检测，如果没有6，7-二氟-3-甲酰基色酮剩余，表明反应完成(此步骤中，中间体6不需要经过分离)。再向反应体系中补加碳酸钾(0.6mmol)，随后将反应体系升温至120℃，反应8小时。通过薄层色谱监测反应，反应完成后，将反应液冷却至室温，向反应液中加入乙酸乙酯，每次15mL，萃取三次。有机相使用无水硫酸钠干燥后，采用柱层析进行分离，得到目标化合物7，产率55％。 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),8.64(s,1H),8.21–8.02(m,2H),4.43(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ188.46,174.58,148.16,137.02,136.92,126.74,116.53,114.05,113.88,108.23,108.01,49.25,14.77.HRMS(ESI)计算值C 12H 10F 2NO 2[M+H] +238.0647，实测值:238.0652。
将化合物7(0.2mmol)溶于水/DCM(3.0mL，1：2)中，称取氨基磺酸/亚氯酸钠各(0.8mmol)加入反应液中。反应在室温下搅拌7小时后，通过薄层色谱检测。如果没有原料剩余，蒸干溶剂，采用柱层析进行分离，得到目标化合物8，产率57％。 1H NMR(400MHz,DMSO-d 6)δ14.87(s,1H),9.09(s,1H),8.43–8.20(m,2H),4.58(q,J＝6.9Hz,2H),1.39(dd,J＝13.0,6.1Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ176.91,166.06,156.00,150.29,137.36,113.96,108.45,108.3,108.22,50.04,14.98.HRMS(ESI)计算值C 12H 10F 2NO 2[M+H] +238.0647，实测值:238.0652。
将化合物8(0.2mmol)，哌嗪(0.22mmol)和三乙胺(0.22mmol)溶于5mL DMSO中。在微波条件下，将反应体系温度升高至微波150℃，搅拌0.5h，通过薄层色谱检测，如果没有原料剩余，将反应液冷却至室温。最后用甲醇重结晶，获得诺氟沙星9，产率59％。 1H NMR(400MHz,DMSO-d 6)δ8.93(s,1H),7.84(d,J＝13.5Hz,1H),7.12(d,J＝7.3Hz,1H),4.58(q,J＝7.0Hz,2H),3.32–3.12(m,4H),3.00–2.69(m,4H),1.42(t,J＝7.1Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ176.54,176.52,166.61,154.58,152.10,148.82,146.53,146.43,137.66,119.43,119.36,111.62,111.40,107.48,105.93,105.90,51.29,51.25,49.47,45.87,14.79.HRMS(ESI)计算值C 16H 19FN 3O 3[M+H] +254.0632，实测值:320.1405。
另外，最后一步反应中，将哌嗪替换为2-甲基哌嗪，在相同的条件下，可以分离得到培氟沙星10，产率66％， 1H NMR(400MHz,DMSO-d 6)δ15.37(s,1H),8.95(s,1H),7.90(d,J＝13.4Hz,1H),7.17(d,J＝7.2Hz,1H),4.59(q,J＝6.9Hz,2H),2.53(s,2H),2.26(s,2H),1.42(t,J＝7.0Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ176.62,166.61,154.28,152.05,148.98,145.89,137.67,119.65,111.73,111.50,107.51,106.28,54.76,49.76,49.51,46.16,14.84.HRMS(ESI)m/z计算值C 17H 21FN 3O 3 +(M+H) +334.1561，实测值334.1563。
实施例3
依伐卡托的合成：
Figure PCTCN2022090989-appb-000022
具体合成依伐卡托的步骤如下：
采用实施例2中的一锅法直接合成关键中间体11，产率71％。 1H NMR(400MHz,CDCl 3)δ10.37(s,1H),8.66(s,1H),8.56(d,J＝7.9Hz,1H),7.92(d,J＝8.8Hz,1H),7.64(t,J＝7.7Hz,1H),7.42(t,J＝7.5Hz,1H),1.84(s,9H). 13C NMR(101MHz,CDCl 3)δ188.66,175.52,142.13,138.40,130.65,129.94,126.95,124.28,119.37,115.09,62.73,29.83.HRMS(ESI)m/z计算值C 14H 16NO 2 +(M+H) +230.1176，实测值230.1177。
将化合物11(0.2mmol)溶于50％HCl/乙腈(5.0mL)溶液中，在80℃下搅拌6小时后，通过薄层色谱检测。如果没有原料剩余，蒸干溶剂，采用柱层析进行分离，得到产物12，产率62％。在实施例2的氧化条件下，将醛基氧化为羧基，得到目标化合物13，产率66％。 1H NMR(400MHz,DMSO-d 6)δ15.36(s,1H),13.51(s,1H),8.90(s,1H),8.30(dd,J＝8.2,1.5Hz,1H),7.89(dd,J＝6.8,1.6Hz,1H),7.88–7.78(m,1H),7.61(td,J＝7.4,6.6,1.3Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ178.79,166.85,145.62,139.90,134.41,126.68,125.51,124.85,120.13,108.02,40.64,40.59,40.43,40.38,40.17,39.96,39.75,39.64,39.54,39.33.HRMS(ESI)m/z calcd for C 14H 15NO 2 +(M+H) +190.0499，实测值190.0501。
称量化合物13(0.2mmol)，O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU,0.24mmol)，三乙胺(0.6mmol)溶于3.0mL DMF中，随后向反应体系中加入2-氨基-3,5-二叔丁基苯酚(0.2mmol)，室温条件下，反应6h。通过薄层色谱检测。如果没有原料剩余，蒸干溶剂， 采用柱层析进行分离，得到依伐卡托14，产率89％。 1H NMR(400MHz,DMSO-d 6)δ12.89(s,1H),11.82(s,1H),9.21(s,1H),8.87(s,1H),8.33(d,J＝8.1Hz,1H),7.85–7.79(m,1H),7.76(d,J＝8.2Hz,1H),7.52(t,J＝7.5Hz,1H),7.17(s,1H),7.10(s,1H),1.38(s,9H),1.36(s,9H). 13C NMR(101MHz,DMSO-d 6)δ176.85,163.27,153.73,144.63,139.61,133.98,133.39,132.73,131.96,126.45,126.03,125.61,124.22,119.58,116.40,111.34,49.06,34.80,34.44,31.03,29.88.HRMS(ESI)计算值C 24H 28N 2O 3[M+H] +393.2173，实测值:393.2171。
实施例4
奥泽沙星前体的合成：
Figure PCTCN2022090989-appb-000023
具体合成奥泽沙星前体的步骤如下：
按照实施例1中合成化合物3的合成方法，可以快速构建奥泽沙星的前体化合物15，产率73％。 1H NMR(400MHz,DMSO-d 6)δ14.69(s,1H),8.87(s,1H),8.06(d,J＝8.6Hz,1H),7.85(d,J＝8.6Hz,1H),4.49–4.31(m,1H),2.92(s,3H),1.22(d,J＝6.3Hz,2H),0.93(s,2H). 13C NMR(101MHz,DMSO-d 6) 13C NMR(101MHz,DMSO)δ178.16,165.79,153.50,143.18,133.92,131.06,129.11,126.60,125.11,108.50,55.58,42.10,23.05,10.82.HRMS(ESI)m/z计算值C 14H 14BrNO 3 +(M+H) +322.0073，实测值322.0076。
实施例5
喹菌酮的合成：
Figure PCTCN2022090989-appb-000024
具体合成喹菌酮的步骤如下：按照实施例1中合成化合物3的方法，最终分离得到喹菌酮16,产率69％。 1H NMR(400MHz,DMSO-d 6)δ15.70(s,1H),8.90(s,1H),7.62(d,J＝11.1Hz,2H),6.30(s,2H),4.54(q,J＝7.0Hz,2H),1.38(t,J＝7.1Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ176.46,166.79,154.20,147.57,137.42,121.88,107.81,103.74,102.33,97.71,50.04,15.09.HRMS(ESI)m/z计算值C 13H 12NO 5 +(M+H) +262.0710，实测值262.0719。
实施例6
由N-叔丁基喹啉酮17合成N-乙基喹啉酮19：
Figure PCTCN2022090989-appb-000025
具体合成N-乙基喹啉酮19的步骤如下：按照实施例2中合成化合物7的合成方法，合成化合物17，产率71％。 1H NMR(400MHz,CDCl 3)δ10.37(s,1H),8.66(s,1H),8.56(d,J＝7.9Hz,1H),7.92(d,J＝8.8Hz,1H),7.64(t,J＝7.7Hz,1H),7.42(t,J＝7.5Hz,1H),1.84(s,9H). 13C NMR(101MHz,CDCl 3)δ188.66,175.52,142.13,138.40,130.65,129.94,126.95,124.28,119.37,115.09,62.73,29.83.HRMS(ESI)m/z计算值C 14H 16NO 2 +(M+H) +230.1176，实测值230.1177。
将化合物17(0.2mmol)溶于50％HCl/MeCN(5.0mL)溶液中,反应温度升至80℃，6小时。经过薄层色谱检测，如果没有原料剩余，蒸干溶剂，得到粗品18。向反应体系中加入碳酸钾(0.6mmol)，碘乙烷(0.22mmol)，DMF(3.0mL)，将反应体系置于100℃条件下，反应3小时。经过薄层色谱检测，如果没有原料剩余，蒸干溶剂，采用柱层析进行分离，得到化合物19，产率92％。 1H NMR(400MHz,CDCl 3)δ10.43(s,1H),8.56(dd,J＝8.0,1.6Hz,1H),8.35(s,1H),7.90–7.68(m,1H),7.57–7.46(m,2H),4.31(q,J＝7.2Hz,2H),1.58(t,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ189.50,176.96,145.50,139.12,133.26,129.70,127.67,125.72,117.28,116.12,77.35,77.23,77.03,76.78,76.71,54.75,49.20,14.56.HRMS(ESI)计算值C 12H 12NO 2[M+H] +202.0863，实测值:202.0867。
上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (12)

  1. 式I化合物的制备方法，其包括如下步骤：
    将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式I化合物，
    Figure PCTCN2022090989-appb-100001
    其中：
    X选自CR 2或N；
    Z选自CR 4或N；
    R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
    R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
    R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
    R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
    R 6独立地选自磺酰基。
  2. 如权利要求1所述的方法，其中：
    所述碱选自无机碱、有机碱、及其组合；或者
    所述碱选自一级胺；
    所述碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、三乙胺、二异丙基胺、二氮杂二环、1,4-二氮杂二环[2.2.2]辛烷、及其组合；或者
    所述碱选自碳酸钾、碳酸铯、碳酸钠、及其组合；或者
    所述反应在溶剂中进行；或者
    所述反应在选自甲醇、乙醇、乙腈、甲苯、水、N,N-二甲基甲酰胺、二甲苯、硝基苯、三氟甲苯、N-甲基吡咯烷酮、1,2-二氯乙烷、1,4-二氧六环、及其组合的溶剂中进行；或者
    所述反应在选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、及其组合的溶剂中进行；或者
    所述反应在80℃-200℃或100℃-150℃的温度下进行。
  3. 式I化合物的制备方法，其包括如下步骤：
    i)将式A化合物与R 5NH 2和R 6Cl在碱的存在下反应生成式B化合物，以及
    ii)将式B化合物在碱的存在下反应生成式I化合物，
    其中步骤ii)的所述反应在高于步骤i)的反应温度的温度下进行；
    Figure PCTCN2022090989-appb-100002
    其中：
    X选自CR 2或N；
    Z选自CR 4或N；
    R 1独立地选自氢、烷基、烷氧基、卤素、NO 2、CN、任选取代的氨基、卤代烷基、芳基和杂芳基；
    R 2和R 3各自独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；或者R 2与R 3连接在一起以形成环；
    R 4独立地选自氢、烷基、烷氧基、卤素、氨基、NO 2、CN、卤代烷基、芳基和杂芳基；
    R 5独立地选自被OH或SH任选取代的烷基、被卤素任选取代的环烷基、芳基和杂芳基；
    R 6独立地选自磺酰基。
  4. 如权利要求3所述的方法，其中：
    所述步骤i)中的碱选自无机碱、有机碱、及其组合；或者
    所述步骤i)中的碱选自一级胺，优选过量的一级胺；或者
    所述步骤i)中的碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、三乙胺、二异丙基胺、二氮杂二环、1,4-二氮杂二环[2.2.2]辛烷、及其组合；或者
    所述步骤i)中的碱选自叔丁醇锂、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、三乙胺、二异丙基胺、二氮杂二环、及其组合；或者
    步骤i)的所述反应在第一溶剂中进行；或者
    步骤i)的所述反应在选自甲醇、乙醇、乙腈、甲苯、水、二甲基亚砜、N,N-二甲基甲酰胺、1,4-二氧六环、及其组合的第一溶剂中进行；或者
    步骤i)的所述反应在室温至150℃或室温至100℃的温度下进行。
  5. 如权利要求3或4所述的方法，其中：
    所述步骤ii)中的碱选自无机碱；或者
    所述步骤ii)中的碱选自碳酸钾、碳酸铯、碳酸钠、氢氧化钠、叔丁醇锂、甲醇钠、碳酸氢钠、钠氢、及其组合；或者
    所述步骤ii)中的碱选自碳酸钾、碳酸铯、碳酸钠、及其组合；或者步骤ii)的所述反应在第二溶剂中进行，或者
    步骤ii)的所述反应在选自二甲苯、硝基苯、三氟甲苯、1,2-二氯乙烷、乙腈、甲苯、二甲基亚砜、N,N-二甲基甲酰胺、1,4-二氧六环、N-甲基吡咯烷酮、及其组合的第二溶剂中进行； 或者
    步骤ii)的所述反应在选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、及其组合的第二溶剂中进行；或者
    步骤ii)的所述反应在100℃-200℃或100℃-150℃的温度下进行。
  6. 如权利要求1至5中任一项所述的方法，其中：
    R 1独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、NO 2、CN、任选取代的氨基、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基；或者
    R 1独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、NO 2、CN、任选取代的氨基、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基；或者
    R 1独立地选自氢、甲基、甲氧基、F、Cl、Br、I、NO 2、CN、CF 3和氨基；或者
    R 1独立地选自氢、烷基和氨基；或者
    R 1独立地选自氢、甲基和氨基；或者
    R 2和R 3各自独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、氨基、NO 2、CN、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基；或R 2与R 3连接在一起以形成3元-12元环，例如5元-12元非芳香族杂环；或者
    R 2和R 3各自独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、氨基、NO 2、CN、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基；或R 2与R 3连接在一起以形成5元-10元环，例如5元-10元非芳香族杂环；或者
    R 2和R 3各自独立地选自氢、甲基、甲氧基、F、Cl、Br、I、氨基、NO 2、CN和CF 3；或者
    R 2和R 3各自独立地选自氢、卤素和氨基；或者
    R 2和R 3各自独立地选自氢和卤素；或者
    R 2和R 3形成5元-7元非芳香族杂环，例如1,3-二氧杂环戊烯；或者
    R 4独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、氨基、NO 2、CN、C 1-6卤代烷基、C 6-12芳基和C 2-12杂芳基；或者
    R 4独立地选自氢、C 1-4烷基、C 1-4烷氧基、卤素、氨基、NO 2、CN、C 1-4卤代烷基、C 6-10芳基和C 2-10杂芳基；或者
    R 4独立地选自氢、甲基、甲氧基、F、Cl、Br、I、NH 2、NO 2、CN和CF 3；或者
    R 4独立地选自氢、烷基、烷氧基、卤素、NH 2和CN；或者
    R 4独立地选自氢、甲基、甲氧基、F、Cl、NH 2和CN；或者
    R 5独立地选自氢、被OH或SH任选取代的C 1-6烷基、被卤素任选取代的3元-12元环烷基、C 6-12芳基和C 2-12杂芳基；或者
    R 5独立地选自被OH或SH任选取代的C 1-6烷基、被卤素任选取代的3元-12元环烷基、C 6-12芳基和C 2-12杂芳基；或者
    R 5独立地选自氢、被OH或SH任选取代的C 1-4烷基、被卤素任选取代的3元-8元环烷基、 C 6-10芳基和C 2-10杂芳基；或者
    R 5独立地选自氢、被OH或SH任选取代的烷基和被卤素任选取代的环烷基；或者
    R 5独立地选自被OH或SH任选取代的烷基、和被卤素任选取代的环烷基；
    R 5独立地选自氢、乙基、环丙烷基、氟代环丙烷基、叔丁基、-(CH 2) 2OH、-(CH 2) 2SH、-CH(CH 3)CH 2OH、和-CH(CH 3)CH 2SH；或者
    R 5独立地选自乙基、环丙烷基、氟代环丙烷基、叔丁基、-(CH 2) 2SH、和-CH(CH 3)CH 2OH；或者
    R 6独立地选自对甲苯磺酰基和乙基磺酰基；或者
    所述卤素选自F、Cl、Br和I；或者
    R 2和R 3中至少之一为卤素；或者
    R 3为卤素；或者
    所述式I化合物选自：
    Figure PCTCN2022090989-appb-100003
  7. 式II化合物的制备方法，其包括如下步骤：
    通过权利要求1-6中任一项所述的方法制得式I化合物；以及
    使式I化合物氧化生成式II化合物，
    Figure PCTCN2022090989-appb-100004
    其中，式II中的X、Z、R 1、R 2、R 3、R 4和R 5的定义与式I中所定义的相同。
  8. 如权利要求7所述的方法，其中所述式II化合物选自：
    Figure PCTCN2022090989-appb-100005
  9. 式III化合物的制备方法，其包括如下步骤：
    通过权利要求7或8所述的方法制得式II化合物；以及
    使式II化合物与任选取代的含氮杂环化合物在碱的存在下反应生成式III化合物,或者使式II化合物发生Stille偶联反应生成式III化合物,
    Figure PCTCN2022090989-appb-100006
    其中：
    在式II中，R 2和R 3不形成环并且R 3为卤素；
    在式III中，X、Z、R 1、R 2、R 4和R 5的定义与式II中所定义的相同，并且R 7选自任选取代 的N-杂环基、任选取代的杂芳基和任选取代的芳基。
  10. 如权利要求9所述的方法，其中：
    所述任选取代的含氮杂环化合物选自被选自任选被NH 2取代的烷基、＝N(烷氧基)、烷氧基、环烷基、羟基、和任选取代的氨基中的一个或多个取代基任选取代的含氮杂环化合物；或者
    所述任选取代的含氮杂环化合物选自各自被选自任选被NH 2取代的C 1-6烷基、＝N(C 1-6烷氧基)、C 1-6烷氧基、3元-7元环烷基、羟基、和NH 2中的一个或多个取代基任选取代的哌啶、哌嗪、四氢吡咯、吡咯并吗啉、吡咯并哌啶、氮杂螺[2.4]庚烷和氮杂环庚烷；其中所述NH 2任选被一个或多个选自C 1-6烷基的基团取代；或者
    R 7选自各自被选自任选被NH 2取代的烷基、＝N(烷氧基)、烷氧基、环烷基、羟基、任选被烷基取代的烷基酰氨基和任选取代的氨基中的一个或多个取代基任选取代的N-杂环基、杂芳基和芳基；或者
    R 7选自各自被选自任选被NH 2取代的C 1-6烷基、＝N(C 1-6烷氧基)、C 1-6烷氧基、3元-7元环烷基、羟基、任选被C 1-6烷基取代的C 1-6烷基酰氨基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的5元-12元N-杂环基、C 2-12杂芳基和C 6-12芳基；或者
    R 7选自被选自任选被NH 2取代的C 1-6烷基、＝N(C 1-6烷氧基)、3元-7元环烷基、羟基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的5元-12元N-杂环基；或者
    R 7选自被选自C 1-6烷基、任选被C 1-6烷基取代的C 1-6烷基酰氨基和被一个或多个C 1-6烷基任选取代的NH 2中的一个或多个取代基任选取代的C 2-12杂芳基；或者
    所述N-杂环基为N-杂环烷基；或者
    R 7选自：
    Figure PCTCN2022090989-appb-100007
  11. 如权利要求9或10所述的方法，其中：
    所述式III化合物选自：
    Figure PCTCN2022090989-appb-100008
  12. 式IV化合物的制备方法，其包括如下步骤：
    通过权利要求7或8所述的方法制得式II化合物；以及
    使式II化合物在合适的条件下反应生成式IV化合物,
    Figure PCTCN2022090989-appb-100009
    其中在式II中，Z为CR 4，R 4为卤素或氨基并且R 5为OH或SH取代的烷基；
    其中在式IV中，X、R 1、R 2和R 3的定义与式II中所定义的相同，并且Y为O或S，R'为烷基；
    其中：
    任选地，R 5为OH或SH取代的C 1-6烷基；或者
    任选地，R 5为OH或SH取代的C 1-4烷基；或者
    任选地，R 5为各自被OH或SH取代的乙基或异丙基；或者
    任选地，所述式IV化合物选自：
    Figure PCTCN2022090989-appb-100010
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