CN116444489A - Quinoline derivative, preparation method and application thereof - Google Patents

Quinoline derivative, preparation method and application thereof Download PDF

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Publication number
CN116444489A
CN116444489A CN202310110464.7A CN202310110464A CN116444489A CN 116444489 A CN116444489 A CN 116444489A CN 202310110464 A CN202310110464 A CN 202310110464A CN 116444489 A CN116444489 A CN 116444489A
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compound
formula
preparation
provides
sodium
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Inventor
臧海山
杨铁
耿文军
张洪英
刘飞
李新路
嵇茜
赵锐
李慧
李超
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN202310110464.7A priority Critical patent/CN116444489A/en
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    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application belongs to the field of medicines, provides a quinoline derivative and a preparation method and application thereof, and particularly relates to an impurity of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine and a preparation method and application thereof.

Description

Quinoline derivative, preparation method and application thereof
Cross Reference to Related Applications
The invention relates to a Chinese application (the invention name is quinoline derivative, the preparation method and the application thereof, the application date is 2018, 12, 29, and the application number is 201811639281. X).
Technical Field
The application belongs to the technical field of medicines, relates to quinoline derivatives and a preparation method and application thereof, and in particular relates to impurities of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine and a preparation method and application thereof.
Background
Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues, play an important role in intracellular signal transduction, and are involved in the regulation, signaling and development of normal cells, and are also closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and can be classified into Epidermal Growth Factor Receptor (EGFR), platelet Derived Growth Factor Receptor (PDGFR), vascular Endothelial Growth Factor Receptor (VEGFR), fibroblast Growth Factor Receptor (FGFR), etc. according to the structure of their extracellular regions.
WO2008112407 discloses in example 24 the compound 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine having the structural formula as shown in formula I:
it is a multi-target receptor tyrosine kinase inhibitor, can inhibit the kinase activities of vascular endothelial cell growth factor receptors (VEGFR 1, VEGFR2/KDR and VEGFR 3), stem cell factor receptors, platelet-derived growth factor receptors and the like, and inhibit the downstream signal transduction mediated by VEGFR2, thereby inhibiting tumor angiogenesis.
Any substance that affects the purity of the drug is collectively referred to as an impurity. Research on impurities is an important content in drug development. In the field of pharmaceutical quality analysis, impurities can be identified or quantitatively analyzed by spectroscopic, chromatographic or other physical methods. The control of the impurity content is extremely important for guaranteeing the safety of medication, and can obviously reduce unknown toxic and side effects. According to the chemical structure characteristics of the medicine, the prescription and process of the preparation, the storage condition and the like, proper acid, alkali, light, heat, oxidation reaction and other accelerated destructive tests can be selected to analyze the possible degradation paths, degradation mechanisms and the like of the medicine.
Before analyzing the impurities in the compound, a substance with higher purity and the same or similar structure as the impurities is required to be used as a reference marker, the relative position of the reference marker in the chromatogram is regarded as the relative position of the impurities in the chromatogram, and the detection of the impurities of the compound to be detected is guided. Obviously, the selection and preparation of the reference marker has a direct influence on the scientificity and accuracy of the detection of the impurity content in the active pharmaceutical ingredient.
Disclosure of Invention
In a first aspect, the present application provides a compound of formula II, having the structure:
in some embodiments, the present invention provides a compound of formula II having a purity of greater than or equal to 90%; in some exemplary embodiments, the present invention provides a compound of formula II having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula II, characterized in that: dissolving a compound of the formula I in a solvent, and adding a methylating agent and a catalyst to prepare the compound of the formula II. Wherein the organic solvent is dichloromethane, chloroform, ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide, methanol or ethanol, preferably dichloromethane; the methylation reagent is dimethyl sulfate or methyl iodide, preferably methyl iodide; the catalyst is pyridine, diethylamine, triethylamine, imidazole, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or calcium hydroxide, preferably triethylamine.
In a second aspect, the present application provides a compound of formula III, having the structure:
in some embodiments, the present invention provides a compound of formula III having a purity of greater than or equal to 90%; in some exemplary embodiments, the present invention provides a compound of formula III having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula III, characterized in that: dissolving a compound of the formula I in a solvent, and adding an ethylation reagent and a catalyst to prepare the compound of the formula III. Wherein the organic solvent is dichloromethane, chloroform, ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide, methanol or ethanol, preferably dichloromethane; the methylating agent is bromoethane, iodoethane and diethyl sulfate, preferably iodoethane; the catalyst is pyridine, diethylamine, triethylamine, imidazole, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or calcium hydroxide, preferably triethylamine.
In a third aspect, the present application provides a compound of formula IV, having the structure:
in some embodiments, the present invention provides a compound of formula IV having a purity of greater than or equal to 90%; in some exemplary embodiments, the present invention provides a compound of formula IV having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula IV, characterized in that: reacting the compound of formula I with an oxidizing agent to obtain a compound of formula IV. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 2-5% hydrogen peroxide solution to prepare a liquid phase for separation to provide the compound of formula IV. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 5% hydrogen peroxide solution to prepare a liquid phase separation to provide the compound of formula IV.
In a fourth aspect, the present application provides a compound of formula V, having the structure:
in some embodiments, the present invention provides a compound of formula V having a purity of greater than or equal to 90%; in some exemplary embodiments, the present invention provides a compound of formula V having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula V, characterized in that: reacting the compound of formula I with an oxidizing agent to obtain a compound of formula V. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 2-5% hydrogen peroxide solution to prepare a liquid phase for separation to provide the compound of formula V. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 3% hydrogen peroxide solution to prepare a liquid phase separation to give the compound of formula V.
In a fifth aspect, the present application provides a compound of formula VI, having the structure:
in some embodiments, the present invention provides a compound of formula VI having a purity of greater than or equal to 90%; in some exemplary embodiments, the present invention provides a compound of formula VI having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula VI comprising:
1) Reacting the compound of formula a with the compound of formula b under alkaline conditions to obtain a compound of formula c;
2) Removing the amino protecting group R from the compound of formula c to obtain the compound of formula VI.
Wherein the amino protecting group R includes, but is not limited to, formyl, acetyl, trifluoroacetyl, benzoyl, p-nitrobenzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, benzyl, p-methoxybenzyl, trityl or tetrahydrofuranyl, preferably benzyloxycarbonyl; l is a leaving group including, but not limited to, p-toluenesulfonyloxy, methanesulfonyloxy, iodine, bromine, chlorine, preferably methanesulfonyloxy, iodine.
The base in step 1) includes, but is not limited to, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, preferably potassium carbonate; solvents include, but are not limited to, acetone, N-dimethylformamide, dimethyl sulfoxide, preferably acetone.
The invention also provides a preparation method of the compound of formula VI, which is characterized in that: reacting the compound of formula I with an oxidizing agent to obtain the compound of formula VI. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 2-5% hydrogen peroxide solution to prepare a liquid phase for separation to provide the compound of formula VI. In some embodiments, the compound of formula I is stirred at room temperature for 24 hours under the action of a 3% hydrogen peroxide solution to prepare a liquid phase separation to provide the compound of formula VI.
In a sixth aspect, the present application provides a compound of formula VII, having the structure:
another partyThe invention provides a preparation method of a compound of formula VII, which is characterized in that: the compound of formula I is placed under illumination to provide a compound of formula VII. In some embodiments, an aqueous solution of a compound of formula I is illuminated for one day (total illuminance of 0.36-0.6X10) at an illuminance of 15000-25000Lx 6 Lx.h), and separating the liquid phase to obtain the compound of the formula VII. In some embodiments, the illuminance condition is 20000Lx, and the illumination is for one day (total illuminance is 0.48×10 6 Lx·h)。
In some embodiments, the solid of the compound of formula I is illuminated for three days at an illuminance of 15000 to 25000Lx (total illuminance of 1.08 to 1.8X10) 6 Lx.h), and separating the liquid phase to obtain the compound of the formula VII. In some embodiments, the illuminance condition is 20000Lx, three days of illumination (total illuminance 1.44×10 6 Lx·h)。
In a seventh aspect, the present application provides a compound of formula VIII, having the structure:
in another aspect, the present invention provides a process for the preparation of a compound of formula VIII, characterized in that: reacting the compound of formula I at an elevated temperature to obtain the compound of formula VIII. In some embodiments, an aqueous solution of a compound of formula I is left at a temperature of 70-90℃for 4 hours to prepare a liquid phase separation to provide a compound of formula VIII. In some embodiments, an aqueous solution of a compound of formula I is left at a temperature of 80 ℃ for 4 hours to prepare a liquid phase separation to provide a compound of formula VIII.
In some embodiments, the solid of the compound of formula I is left at a temperature of 100-110℃for 48 hours, and a liquid phase separation is prepared to give the compound of formula VIII. In some embodiments, a solid of the compound of formula I is left at a temperature of 105 ℃ for 48 hours, and a liquid phase separation is prepared to give the compound of formula VIII.
In another aspect, the invention also provides the use of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII and/or a compound of formula VIII as a standard or control; in some embodiments, there is provided the use of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII and/or a compound of formula VIII as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula II having a purity of ≡90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula II having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula III having a purity of > 90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula III having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula IV having a purity of ≡90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula IV having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula V having a purity of > 90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula V having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula VI having a purity of ≡90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula VI having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula VII having a purity of ≡90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula VII having a purity of 95% or more as a reference marker when the compound of formula I is checked for impurities.
In some embodiments, the present invention provides the use of a compound of formula VIII having a purity of ≡90% as a reference marker in the detection of impurities in a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula VIII having a purity of greater than or equal to 95% as a reference marker when the compound of formula I is checked for impurities.
Detailed Description
The technical scheme of the application is described by specific embodiments, but the protection scope of the application is not limited to the following embodiments. The reagents used were all commercially available. 1 HNMR spectra were run at 500MHz in the solvents shown and recorded. The following abbreviations are used: s, unimodal; d, double peaks; t, triplet; m, multiple peaks.
EXAMPLE 1 preparation of Compounds of formula II
Into a 500mL glass reaction flask, 10.0g of the compound of formula I, 3.7g of triethylamine and 200mL of methylene chloride were sequentially charged. 3.8g of methyl iodide is added dropwise at the temperature of between 0 and 10 ℃, the reaction is carried out for 2 hours at room temperature after the dropwise addition, then purified water is added, the mixture is stirred for 10 minutes, the mixture is kept stand for 10 minutes, an organic phase is separated out, anhydrous sodium sulfate is dried and then concentrated to dryness, and then a liquid phase is prepared for separation, so that the compound of the formula II is obtained.
LC-MS：m/z：422.1874[M+H] + 。
EXAMPLE 2 preparation of Compounds of formula III
Into a 500mL glass reaction flask, 10.0g of the compound of formula I, 3.7g of triethylamine and 200mL of methylene chloride were sequentially charged. And (3) dropwise adding 4.1g of ethyl iodide at the temperature of between 0 and 10 ℃, reacting for 2 hours at room temperature after the dropwise adding is finished, adding purified water, stirring for 10 minutes, standing for 10 minutes, separating out an organic phase, drying with anhydrous sodium sulfate, concentrating to dryness, and preparing a liquid phase for preparation and separation to obtain the compound shown in the formula III.
1 HNMR：δ11.71(1H,s),8.42(1H,d),7.61(1H,s),7.41(1H,s),7.22(1H,d),7.00(1H,t),6.33(1H,d),6.28(1H,s),4.14(2H,s),3.99(3H,s),2.74(2H,q),2.43(3H,s),1.00(3H,t),0.68(4H,m)；LC-MS：m/z：436.2031[M+H]+。
EXAMPLE 3 preparation of Compounds of formula IV
Taking 10g of the compound of the formula I, stirring for 24 hours at room temperature under the action of 300ml of 3% hydrogen peroxide solution, and then preparing a liquid phase for separation to obtain the compound of the formula IV.
1 HNMR：δ8.47(d,1H),7.84(s,1H),7.53(m,2H),7.37(s,1H),6.64(d,1H),6.47(d,1H),4.05(s,2H),3.97(s,3H),1.35(s,3H),0.60-0.66(m,4H)。
LC-MS：m/z：440.1616[M+H] + 。
EXAMPLE 4 preparation of Compounds of formula V
Taking the compound of the formula I, stirring for 24 hours at room temperature under the action of 3% hydrogen peroxide solution, and then preparing a liquid phase for separation to obtain the compound of the formula V.
1 HNMR：δ12.24(s,1H),8.47(d,1H),8.19(d,1H),7.59(s,1H),7.46(s,1H),7.29(t,1H),6.42(d,1H),4.29(s,2H),3.98(s,3H),2.06(s,3H),0.98-1.09(m,4H)。LC-MS：m/z：456.1565[M+H] + 。
EXAMPLE 5 preparation of Compounds of formula VI
Into a 500mL glass reaction flask, 10.0g of 6-methoxyquinoline-4, 7-diol (compound of formula a), 20g of potassium carbonate, 20g of potassium iodide and 200mL of acetone were sequentially charged. The reaction mixture was warmed to reflux, a total of 20g of methyl 1- (((benzyloxycarbonyl) amino) cyclopropyl) methylsulfonate (compound of formula b 1) was added in portions, and the reaction was allowed to proceed for 40 hours, and TLC trace showed that the reaction was complete. The reaction solution was concentrated to dryness, then purified water and methylene chloride were added, after stirring for 10 minutes, after standing for 10 minutes, an organic phase was separated, dried over anhydrous sodium sulfate, and then concentrated to dryness, followed by column chromatography to obtain the compound benzyl (1- (((4-hydroxy-6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate (compound of formula c 1).
2.0g of the compound of formula c1, 0.6g of 10% palladium on carbon, 1.0g of ammonium formate and 20mL of methanol were put into a 100mL glass reaction flask in this order. The reaction was incubated at 45-55deg.C, TLC tracing showed complete reaction, filtration, washing the filter cake with a small amount of methanol, concentrating the filtrate under reduced pressure to dryness, then adding purified water and dichloromethane, stirring for 10min, standing for 10min, separating out the organic phase, drying over anhydrous sodium sulfate, concentrating to dryness, and then separating by column chromatography to obtain the compound of formula VI.
LC-MS：m/z：261.1234[M+H] + 。
EXAMPLE 6 preparation of Compounds of formula VII
The aqueous solution of the compound of formula I was irradiated for one day at an illuminance of 20000Lx (total illuminance of 0.48X10) 6 Lx.h), and separating the liquid phase to obtain the compound of formula VII. Wherein a liquid phase is prepared, and the chromatographic column is Thermo HYPERSIL BDS C (4.6X105 mm,5 μm), or the chromatographic column has equivalent efficacy; the mobile phase A is ammonium formate solution, ammonia water is added, the pH value is regulated to 3.5 by formic acid, and the mobile phase B is acetonitrile for gradient elution.
LC-MS：m/z：422.1511[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the Secondary fragment m/z:353.0934.
EXAMPLE 7 preparation of Compounds of formula VIII
The aqueous solution of the compound of formula I is left at 80℃for 4 hours to prepare a liquid phase which is separated to give the compound of formula VIII. Wherein, the liquid phase is prepared, and the adopted chromatographic column is: thermo HYPERSIL BDS C18 (4.6X250 mm,5 μm), or a column of comparable performance; the mobile phase A is ammonium formate solution, ammonia water is added, the pH value is regulated to 3.5 by formic acid, and the mobile phase B is acetonitrile for gradient elution.
LC-MS：m/z：827.3428[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the Secondary fragment m/z:414.1718.

Claims (12)

1. a compound of formula II, having the structure:
2. a compound of formula III, having the structure:
3. a compound of formula IV having the structure:
4. a compound of formula V, having the structure:
5. a compound of formula VI, having the structure:
6. a compound of formula VII, having the structure:
7. a compound of formula VIII, having the structure:
8. a process for the preparation of a compound of formula II, characterized in that: dissolving a compound of the formula I in a solvent, and adding a methylating agent and a catalyst to prepare the compound of the formula II, wherein the methylating agent is dimethyl sulfate or methyl iodide, and preferably methyl iodide; the catalyst is pyridine, diethylamine, triethylamine, imidazole, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or calcium hydroxide, preferably triethylamine.
9. A process for preparing a compound of formula VI comprising:
1) Reacting the compound of formula a with the compound of formula b under alkaline conditions to obtain a compound of formula c;
2) Removing amino protecting groups R from the compound of the formula c to obtain a compound of the formula VI;
wherein the amino protecting group R includes, but is not limited to, formyl, acetyl, trifluoroacetyl, benzoyl, p-nitrobenzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, benzyl, p-methoxybenzyl, trityl or tetrahydrofuranyl, preferably benzyloxycarbonyl;
l is a leaving group including, but not limited to, p-toluenesulfonyloxy, methanesulfonyloxy, iodine, bromine, chlorine, preferably methanesulfonyloxy, iodine.
10. The process according to claim 9, characterized in that the base in step 1) is sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis trimethylsilylamide, sodium bis (trimethylsilyl) amide, preferably potassium carbonate.
11. Use of a compound of formula II according to claim 1, a compound of formula III according to claim 2, a compound of formula IV according to claim 3, a compound of formula V according to claim 4, a compound of formula VI according to claim 5, a compound of formula VII according to claim 6 and/or a compound of formula VIII according to claim 7 as a standard or control.
12. Use of a compound of formula II according to claim 1, a compound of formula III according to claim 2, a compound of formula IV according to claim 3, a compound of formula V according to claim 4, a compound of formula VI according to claim 5, a compound of formula VII according to claim 6 and/or a compound of formula VIII according to claim 7 as a reference marker in the impurity inspection of a compound of formula I.
CN202310110464.7A 2018-12-29 2018-12-29 Quinoline derivative, preparation method and application thereof Pending CN116444489A (en)

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US8148532B2 (en) * 2007-03-14 2012-04-03 Guoqing Paul Chen Spiro substituted compounds as angiogenesis inhibitors
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