CN109705093A - Quinoline and its preparation method and application - Google Patents

Quinoline and its preparation method and application Download PDF

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Publication number
CN109705093A
CN109705093A CN201811639281.XA CN201811639281A CN109705093A CN 109705093 A CN109705093 A CN 109705093A CN 201811639281 A CN201811639281 A CN 201811639281A CN 109705093 A CN109705093 A CN 109705093A
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formula
compound
group
follows
preparation
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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
Priority to CN201811639281.XA priority patent/CN109705093A/en
Publication of CN109705093A publication Critical patent/CN109705093A/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 field of medicaments, there is provided a kind of quinoline and its preparation method and application, and in particular to the impurity and its preparation method and application of 1- ((4- (the fluoro- 2- Methyl-1H-indole -5- base oxygroup of 4-) -6- methoxy quinoline -7- base oxygroup) methyl) cyclopropylamine.

Description

Quinoline and its preparation method and application
Technical field
The application belongs to pharmaceutical technology field, is related to quinoline and its preparation method and application, and in particular to 1- The impurity of ((4- (the fluoro- 2- Methyl-1H-indole -5- base oxygroup of 4-) -6- methoxy quinoline -7- base oxygroup) methyl) cyclopropylamine and Preparation method and use.
Background technique
Tyrosine kinase is the enzyme of one group of catalytic proteins tyrosine residue phosphorylation, is risen in signal transduction in the cell Important role, it participate in normal cell adjusting, signal transmitting and development, also with the proliferation of tumour cell, differentiation, migration It is closely related with apoptosis.Many receptor tyrosine kinases are all related to the formation of tumour, not according to its extracellular space structure It is same to be divided into EGF-R ELISA (EGFR), PDGF recepter (PDGFR), vascular endothelial cell growth Factor acceptor (VEGFR), fibroblast growth factor acceptor (FGFR) etc..
WO2008112407 discloses compound 1- ((4- (the fluoro- 2- Methyl-1H-indole -5- base oxygen of 4- in embodiment 24 Base) -6- methoxy quinoline -7- base oxygroup) methyl) cyclopropylamine and preparation method thereof, its structural formula is shown in formula I:
It is the receptor tyrosine kinase inhibitors of a multiple target point, can inhibit vascular endothelial growth factor receptor The kinase activities such as (VEGFR1, VEGFR2/KDR and VEGFR3), stem cell factor receptor, platelet-derived growth factor receptor, suppression The downstream signal transduction that VEGFR2 processed is mediated, to inhibit tumor angiogenesis.
The substance of any influence pharmaceutical purity is referred to as impurity.Miscellaneous Quality Research is an important content of drug research and development. In medicine quality analysis technical field, spectrum, chromatography or the identification of other physical methods or quantitative analysis is can be used in impurity.Control The content of impurity is of crucial importance for the safety for ensureing medication, can significantly reduce unknown toxicity.According to the change of drug The acceleration such as suitable acid, alkali, light, heat, oxidation reaction can be selected in the prescription and technique, condition of storage etc. for learning design feature, preparation Destructive testing carries out the possible degradation pathway of analysis drug and degradation mechanism etc..
Before analyzing the impurity in compound, needs higher using purity and there is identical or phase with above-mentioned impurity The substance of nearly structure is considered as impurity in chromatogram as reference marker, and by relative position of the reference marker in chromatogram In relative position, and defects inspecting of compound to be checked is instructed with this.Obviously, the selection and system of reference marker Standby, the science and accuracy detect on impurity content in active pharmaceutical ingredient has direct influence.
Summary of the invention
In a first aspect, this application provides a kind of Formula II compound, structure are as follows:
In some embodiments, the present invention provides a kind of Formula II compounds of purity >=90%；Some typical In embodiment, the present invention provides a kind of Formula II compounds of purity >=95%.
On the other hand, the present invention provides a kind of preparation methods of Formula II compound, it is characterised in that: by compound of formula I It is dissolved in solvent, methylating reagent and catalyst is added, Formula II compound is prepared.Wherein, the organic solvent is two Chloromethanes, chloroform, ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide, methanol or ethyl alcohol, preferably methylene chloride； The methylating reagent is dimethyl suflfate or iodomethane, preferably iodomethane；The catalyst be pyridine, diethylamine, Triethylamine, imidazoles, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, hydroxide Sodium or calcium hydroxide, preferably triethylamine.
Second aspect, this application provides a kind of formula III compound, structures are as follows:
In some embodiments, the present invention provides a kind of formula III compounds of purity >=90%；Some typical In embodiment, the present invention provides a kind of formula III compounds of purity >=95%.
On the other hand, the present invention provides a kind of preparation methods of formula III compound, it is characterised in that: by compound of formula I It is dissolved in solvent, ethylating agent and catalyst is added, formula III compound is prepared.Wherein, the organic solvent is two Chloromethanes, chloroform, ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide, methanol or ethyl alcohol, preferably methylene chloride； The methylating reagent is bromoethane, iodoethane, dithyl sulfate, preferably iodoethane；The catalyst is pyridine, two Ethamine, triethylamine, imidazoles, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, Sodium hydroxide or calcium hydroxide, preferably triethylamine.
The third aspect, this application provides a kind of formula IV compound, structures are as follows:
In some embodiments, the present invention provides a kind of formula IV compounds of purity >=90%；Some typical In embodiment, the present invention provides a kind of formula IV compounds of purity >=95%.
On the other hand, the present invention provides a kind of preparation methods of formula IV compound, it is characterised in that: by compound of formula I With oxidant reaction, formula IV compound is obtained.In some embodiments, molten in the hydrogen peroxide of 2-5% by compound of formula I Under liquid effect, it is stirred at room temperature for 24 hours, prepares liquid phase separation, obtain formula IV compound.In some embodiments, by Formulas I chemical combination Object is stirred at room temperature for 24 hours under 5% hydrogenperoxide steam generator effect, prepares liquid phase separation, obtain formula IV compound.
Fourth aspect, this application provides a kind of Formula V compound, structures are as follows:
In some embodiments, the present invention provides a kind of Formula V compounds of purity >=90%；In some typical realities It applies in scheme, the present invention provides a kind of Formula V compounds of purity >=95%.
On the other hand, the present invention provides a kind of preparation methods of Formula V compound, it is characterised in that: by compound of formula I with Oxidant reaction obtains Formula V compound.In some embodiments, by compound of formula I, make in the hydrogenperoxide steam generator of 2-5% Under, it is stirred at room temperature for 24 hours, prepares liquid phase separation, obtain Formula V compound.In some embodiments, by compound of formula I, Under 3% hydrogenperoxide steam generator effect, it is stirred at room temperature for 24 hours, prepares liquid phase separation, obtain Formula V compound.
5th aspect, this application provides a kind of Formula IV compound, structures are as follows:
In some embodiments, the present invention provides a kind of Formula IV compounds of purity >=90%；Some typical In embodiment, the present invention provides a kind of Formula IV compounds of purity >=95%.
On the other hand, the present invention provides a kind of preparation methods of Formula IV compound, comprising:
1) after formula a compound and formula b compound react under alkaline condition, formula c compound is obtained；
2) formula c compound sloughs amino protecting group R, obtains Formula IV compound.
Wherein, amino protecting group R includes but is not limited to formoxyl, acetyl group, trifluoroacetyl group, benzoyl, p- nitro Benzoyl, ptoluene-sulfonyl, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, p- methoxyl group benzyloxy carbonyl Base, trichloro-ethoxycarbonyl, benzyl, p- methoxy-benzyl, trityl or tetrahydrofuran base, preferably benzyloxycarbonyl group；L be from Remove group, including but not limited to tolysulfonyl oxygroup, mesyloxy, iodine, bromine, chlorine, preferably mesyloxy, iodine.
Alkali in step 1) includes but is not limited to sodium carbonate, potassium carbonate, sodium hydride, hydrofining, lithium diisopropylamine, double Trimethyl silicon substrate amido lithium, bis- (trimethyl silicon substrate) Sodamides, preferably potassium carbonate；Solvent includes but is not limited to acetone, N, N- bis- Methylformamide, dimethyl sulfoxide, preferably acetone.
The present invention also provides a kind of preparation methods of Formula IV compound, it is characterised in that: by compound of formula I and oxidant Reaction, obtains Formula IV compound.In some embodiments, by compound of formula I, under the hydrogenperoxide steam generator effect of 2-5%, It is stirred at room temperature for 24 hours, prepares liquid phase separation, obtain Formula IV compound.In some embodiments, by compound of formula I, 3% Under hydrogenperoxide steam generator effect, it is stirred at room temperature for 24 hours, prepares liquid phase separation, obtain Formula IV compound.
6th aspect, this application provides a kind of Formula VII compound, structures are as follows:
On the other hand, the present invention provides a kind of preparation methods of Formula VII compound, it is characterised in that: by compound of formula I It places under light illumination, obtains Formula VII compound.In some embodiments, by the aqueous solution of compound of formula I, it is in illuminance Under conditions of 15000-25000Lx, (total illumination is 0.36-0.6 × 10 within one day for illumination6Lxh), liquid phase separation is prepared, is obtained Formula VII compound.In some embodiments, level conditions 20000Lx, illumination one day (total illumination is 0.48 × 106Lx·h)。
In some embodiments, by compound of formula I solid, under conditions of illuminance is 15000-25000Lx, illumination (total illumination is 1.08-1.8 × 10 within three days6Lxh), liquid phase separation is prepared, Formula VII compound is obtained.In some embodiments In, level conditions 20000Lx, (total illumination is 1.44 × 10 everyday for illumination three6Lx·h)。
7th aspect, this application provides a kind of Formula VIII compound, structures are as follows:
On the other hand, the present invention provides a kind of preparation methods of Formula VIII compound, it is characterised in that: by Formulas I chemical combination Object reacts at high temperature, obtains Formula VIII compound.In some embodiments, by the aqueous solution of compound of formula I, in 70-90 It at a temperature of DEG C, places 4 hours, prepares liquid phase separation, obtain Formula VIII compound.In some embodiments, by Formulas I chemical combination The aqueous solution of object, 80 DEG C at a temperature of, place 4 hours, prepare liquid phase separation, obtain Formula VIII compound.
In some embodiments, by compound of formula I solid 100-110 DEG C at a temperature of, place 48 hours, preparation solution It mutually separates, obtains Formula VIII compound.In some embodiments, by compound of formula I solid 105 DEG C at a temperature of, place 48 hours, liquid phase separation is prepared, Formula VIII compound is obtained.
On the other hand, the present invention also provides Formula II compound, formula III compound, formula IV compound, Formula V compounds, formula VI compound, Formula VII compound and/or Formula VIII compound are used as the purposes of standard items or reference substance；In some embodiment party In case, Formula II compound, formula III compound, formula IV compound, Formula V compound, Formula IV compound, Formula VII compound are provided And/or purposes of the Formula VIII compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of Formula II compounds of purity >=90% in compound of formula I As the purposes of reference marker when determination of foreign matter；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% Formula II compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of formula III compounds of purity >=90% in compound of formula I As the purposes of reference marker when determination of foreign matter；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% formula III compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of formula IV compounds of purity >=90% in compound of formula I As the purposes of reference marker when determination of foreign matter；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% formula IV compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of Formula V compounds of purity >=90% in the miscellaneous of compound of formula I As the purposes of reference marker when quality inspection is looked into；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% Formula V compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of Formula IV compounds of purity >=90% in compound of formula I As the purposes of reference marker when determination of foreign matter；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% Formula IV compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of Formula VII compounds of purity >=90% in compound of formula I As the purposes of reference marker when determination of foreign matter；In some typical embodiments, the present invention provides a kind of purity >= Purposes of the 95% Formula VII compound in the determination of foreign matter of compound of formula I as reference marker.
In some embodiments, the present invention provides a kind of Formula VIII compounds of purity >=90% in compound of formula I Determination of foreign matter when purposes as reference marker；In some typical embodiments, the present invention provides a kind of purity Purposes of >=95% Formula VIII compound in the determination of foreign matter of compound of formula I as reference marker.
Specific embodiment
Illustrate the technical solution of the application with specific embodiment, but the protection scope of the application is not limited to following implementation Example range.Used reagent is commercial product.1HNMR wave spectrum operates and is remembered in 500MHz in the solvent shown in Record.Use following abbreviations: s, it is unimodal；D, it is bimodal；T, triplet；M, multiplet.
The preparation of 1 Formula II compound of embodiment
Compound of formula I 10.0g, triethylamine 3.7g and methylene chloride 200ml are successively put into 500mL glass reaction bottle. Iodomethane 3.8g is added dropwise between 0-10 DEG C, 2h is reacted at room temperature after being added dropwise, purified water is added later, it is quiet after stirring 10min After setting 10min, organic phase is separated, is concentrated to dryness after anhydrous sodium sulfate is dry, is prepared liquid phase preparative separation later, formula is prepared II compound.
LC-MS:m/z:422.1874 [M+H]+。
The preparation of 2 formula III compound of embodiment
Compound of formula I 10.0g, triethylamine 3.7g and methylene chloride 200ml are successively put into 500mL glass reaction bottle. Iodoethane 4.1g is added dropwise between 0-10 DEG C, 2h is reacted at room temperature after being added dropwise, purified water is added later, it is quiet after stirring 10min After setting 10min, organic phase is separated, is concentrated to dryness after anhydrous sodium sulfate is dry, is prepared liquid phase preparative separation later, formula is prepared III compound.
1HNMR: δ 11.71 (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]+.
The preparation of 3 formula IV compound of embodiment
Modus ponens Compound I 10g is stirred at room temperature for 24 hours, later preparation solution under 3% hydrogenperoxide steam generator 300ml effect It mutually separates, formula IV compound is prepared.
1HNMR: δ 8.47 (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]+。
The preparation of 4 Formula V compound of embodiment
Modus ponens Compound I is stirred at room temperature for 24 hours under 3% hydrogenperoxide steam generator effect, prepares liquid phase separation later, make It is standby to obtain Formula V compound.
1HNMR: δ 12.24 (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]+。
The preparation of 5 Formula IV compound of embodiment
6- methoxy quinoline -4,7- glycol (formula a compound) 10.0g, carbonic acid are successively put into 500mL glass reaction bottle Potassium 20g, potassium iodide 20g and acetone 200ml.Reaction solution is warming up to reflux, 1- (((benzyloxycarbonyl group) amino) cyclopropyl is added portionwise Base) methyl methylsulfonate (formula b1 compound) total 20g, reacts 40h, TLC tracking display fully reacting.Reaction solution is concentrated into It is dry, purified water and methylene chloride are added later, after stirring 10min, after standing 10min, separates organic phase, anhydrous sodium sulfate is dry After be concentrated to dryness, column chromatography for separation obtains compound benzyl (1- (((4- hydroxyl -6- methoxy quinoline -7- base) oxygroup) first later Base) cyclopropyl) carbamate (formula c1 compound).
The successively throw-in type c1 compound 2.0g in 100mL glass reaction bottle, 10% palladium carbon 0.6g, ammonium formate 1.0g and first Alcohol 20ml.In 45-55 DEG C of insulation reaction, TLC tracking display fully reacting is filtered, and filter cake is washed with a small amount of methanol, filtrate decompression It is concentrated to dryness, purified water and methylene chloride is added later, after stirring 10min, after standing 10min, separate organic phase, anhydrous slufuric acid It is concentrated to dryness after sodium is dry, column chromatography for separation obtains Formula IV compound later.
LC-MS:m/z:261.1234 [M+H]+。
The preparation of 6 Formula VII compound of embodiment
By the aqueous solution of compound of formula I, in the case where illumination is 20000Lx, (total illumination is 0.48 × 10 within one day for illumination6Lx· H), liquid phase separation is prepared, Formula VII compound is prepared.Liquid phase is wherein prepared, the chromatographic column used is Thermo HYPERSIL BDS C18 (4.6 × 250mm, 5 μm) or the suitable chromatographic column of efficiency；Mobile phase A is ammonium formate solution, and ammonia is added Water, first acid for adjusting pH to 3.5, Mobile phase B are that acetonitrile carries out gradient elution.
LC-MS:m/z:422.1511 [M+H]+；Secondary fragment m/z:353.0934.
The preparation of 7 Formula VIII compound of embodiment
By the aqueous solution of compound of formula I, 80 DEG C at a temperature of, place 4 hours, prepare liquid phase separation, obtain Formula VIII Compound.Liquid phase is wherein prepared, the chromatographic column used is chromatographic column: Thermo HYPERSIL BDS C18 (4.6 × 250mm, 5 μm) or the suitable chromatographic column of efficiency；Mobile phase A is ammonium formate solution, ammonium hydroxide is added, first acid for adjusting pH to 3.5, Mobile phase B is second Nitrile carries out gradient elution.
LC-MS:m/z:827.3428 [M+H]+；Secondary fragment m/z:414.1718.

Claims (10)

1. a kind of Formula II compound, structure are as follows:
2. a kind of formula III compound, structure are as follows:
3. a kind of formula IV compound, structure are as follows:
4. a kind of Formula V compound, structure are as follows:
5. a kind of Formula IV compound, structure are as follows:
6. a kind of Formula VII compound, structure are as follows:
7. a kind of Formula VIII compound, structure are as follows:
8. a kind of preparation method of Formula II compound, it is characterised in that: compound of formula I is dissolved in solvent, methylation examination is added Formula II compound is prepared in agent and catalyst, wherein the methylating reagent is dimethyl suflfate or iodomethane, preferably Iodomethane；The catalyst be pyridine, diethylamine, triethylamine, imidazoles, 4-aminopyridine, 4-dimethylaminopyridine, piperazine, Morpholine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or calcium hydroxide, preferably triethylamine.
9. a kind of preparation method of Formula IV compound, comprising:
1) after formula a compound and formula b compound react under alkaline condition, formula c compound is obtained；
2) formula c compound sloughs amino protecting group R, obtains Formula IV compound；
Wherein, amino protecting group R includes but is not limited to formoxyl, acetyl group, trifluoroacetyl group, benzoyl, p- nitrobenzoyl Acyl group, ptoluene-sulfonyl, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, p- methbxybenzyl-oxycarbonyl, three Chloroethene oxygen carbonyl, benzyl, p- methoxy-benzyl, trityl or tetrahydrofuran base, preferably benzyloxycarbonyl group；
L is leaving group, including but not limited to tolysulfonyl oxygroup, mesyloxy, iodine, bromine, chlorine, preferably methylsulphur acyl-oxygen Base, iodine.
10. the preparation method of claim 9, it is characterised in that alkali described in step 1) be sodium carbonate, potassium carbonate, sodium hydride, Hydrofining, lithium diisopropylamine, lithium hexamethyldisilazide, bis- (trimethyl silicon substrate) Sodamides, preferably potassium carbonate.
CN201811639281.XA 2018-12-29 2018-12-29 Quinoline and its preparation method and application Pending CN109705093A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102356063A (en) * 2009-03-16 2012-02-15 Eos伦理肿瘤学公司（简称“Eos公司”） A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof
CN105837559A (en) * 2007-03-14 2016-08-10 南京爱德程医药科技有限公司 Spiro substituted compounds as angiogenesis inhibitors
CN107778288A (en) * 2016-08-26 2018-03-09 正大天晴药业集团股份有限公司 A kind of impurity of quinoline and its production and use
CN107778290A (en) * 2016-08-30 2018-03-09 正大天晴药业集团股份有限公司 A kind of impurity of quinoline and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105837559A (en) * 2007-03-14 2016-08-10 南京爱德程医药科技有限公司 Spiro substituted compounds as angiogenesis inhibitors
CN102356063A (en) * 2009-03-16 2012-02-15 Eos伦理肿瘤学公司（简称“Eos公司”） A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof
CN107778288A (en) * 2016-08-26 2018-03-09 正大天晴药业集团股份有限公司 A kind of impurity of quinoline and its production and use
CN107778290A (en) * 2016-08-30 2018-03-09 正大天晴药业集团股份有限公司 A kind of impurity of quinoline and preparation method thereof

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