CN105017145B - 7-chloro-4-oxo-quinoline derivative with antitumor activity - Google Patents

7-chloro-4-oxo-quinoline derivative with antitumor activity Download PDF

Info

Publication number
CN105017145B
CN105017145B CN201510393896.9A CN201510393896A CN105017145B CN 105017145 B CN105017145 B CN 105017145B CN 201510393896 A CN201510393896 A CN 201510393896A CN 105017145 B CN105017145 B CN 105017145B
Authority
CN
China
Prior art keywords
chloro
compound
cdcl
nmr
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510393896.9A
Other languages
Chinese (zh)
Other versions
CN105017145A (en
Inventor
王子厚
曹日晖
张晓东
荣祖元
陈西敬
张训缨
黄汉源
李忠野
徐�明
王忠奎
李键茹
任政华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CN201510393896.9A priority Critical patent/CN105017145B/en
Publication of CN105017145A publication Critical patent/CN105017145A/en
Application granted granted Critical
Publication of CN105017145B publication Critical patent/CN105017145B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said 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
    • 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

Abstract

The present invention relates to the 7-chloro-4-oxo-quinoline derivative with antitumor activity, in particular it relates to compound of formula I：And its pharmaceutically acceptable salt, solvate, prodrug, wherein R1Selected from hydrogen, C1‑6Alkyl, C2‑6Alkenyl, C2‑6Alkynyl, C1‑6Alkyl phenyl, wherein described alkyl, alkenyl, alkynyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl, C1‑6Alkoxy, phenyl substitution；R3Selected from hydrogen, CONHR31、‑COOR32, wherein the R31And R32It is each independently selected from C1‑6Alkyl and C1‑6Alkyl amino, wherein the amino is optionally by 1~2 C1‑6Alkyl substitutes；R7Selected from halogen, C1‑6Alkoxy, morpholinyl or piperazinyl.

Description

7-chloro-4-oxo-quinoline derivative with antitumor activity
The application is the divisional application for the Chinese Patent Application No. 2013106521915 submitted on December 5th, 2013, and its is complete Portion's content is incorporated herein by reference.
Technical field
The present invention relates to a kind of 7-chloro-4-oxo-quinoline derivative with antitumor activity, the system of such 7-chloro-4-oxo-quinoline derivative is further related to Preparation Method, and their applications in anti-tumor drug is prepared.
Background technology
The chloro- 4- oxo-quinolines of 7-, are typically known as 7-chloro-4-oxo-quinoline, molecular formula is：C9H6ClNO, molecular weight：179.6 Fusing point is 282-285 DEG C, and character is as follows for white or off-white powder, its chemical structural formula：
The compound has tautomerism, and its dynamic isomer is 7- chloro-4-hydroxyls-quinoline, and the two variation relation is such as Under：
Known 7-chloro-4-oxo-quinoline is the national PTS that Tonghua, Jilin Province Mao Xiang pharmaceutical Co. Ltds voluntarily develop, categoryization Learn the medicine first kind.The medicine is put into national " 1035 " engineering and national " 95 " program for tackling key problems in science and technology；In April, 2002, pass through Department of Science and Technology's Life Sci-Tech centre of development is checked and accepted；In September, 2002, obtain " the patent of invention that State Intellectual Property Office issues Certificate ".Obtain on April 23rd, 2003 two New Drug Certificates (bulk drug and capsule) for issuing of National Drug Administration and Two drug registration official written replies.
Early in nineteen forty-six, Hammer and Surrey are just reported using m-chloroaniline and methyl-oxalacetic ester as raw material, warp Method (J.Am.Chem.Soc.68 (1946) 113- of the reactions such as condensation, closed loop, decarboxylation synthesis 7- chloro-4-hydroxyls-quinoline 116).Then, Roberts and Price reports a kind of higher synthetic route of yield, i.e., with m-chloroaniline and ethyoxyl methylene Propylmalonic acid dimethyl ester is raw material, the method that 7- chloro-4-hydroxyls-quinoline is synthesized through reactions such as condensation, cyclization, depicklings, and three steps are anti- The total recovery answered is up to 75% (J.Am.Chem.Soc.68 (1946) 1204-1208).Compared with former approach, this method has The advantages of two aspects：(1) isomers that ring closure reaction does not have 5- chlorine to substitute produces；(2) overall yield of reaction is high.2009, Langer etc. reports an easier synthetic route, i.e., using m-chloroaniline and isopropylidene malonate as raw material, through condensation 7- chloro-4-hydroxyls-quinoline is can obtain with cyclization two-step reaction, the route is for having symmetrical substitution halogen atom on phenyl ring Aniline raw material, yield is higher, but this method can then generate 5 substituted isomers for the mono-substituted aniline of phenyl ring (Synthesis 1(2009)69-78)。
7-chloro-4-oxo-quinoline is used for clinical antineoplastic at present in the form of oral capsule and treated, and clinic confirms that it has wider antitumor spectra, It is more notable particularly with advanced breast cancer and non-small cell lung cancer, life cycle can be obviously prolonged, is improved the quality of living, and is had Toxicity is slight, bone marrow suppression and immunosuppressive action without general anticarcinogen, it is convenient to take the characteristics of.
Also become apparent from addition, taking 7-chloro-4-oxo-quinoline patient curative effect when receiving radiotherapy, analysis may be provided simultaneously with radiating The effect of enhanced sensitivity.
The Anticancer Effect and Mechanism of 7-chloro-4-oxo-quinoline is to cause lysosome in cancer cell by the damage to DNA of tumor cell template Increase increases, and causes to rupture, and discharges a variety of hydrolases, so as to cause cancer cell self-dissolving dead.
However, 7-chloro-4-oxo-quinoline presently, there are both sides problem as a kind of antitumor original new drug of China's chemistry：(1) chlorine Oxygen quinoline bulk drug solubility very little in water, so can not be clinically administered in the form of injection.Clinically use at present The dosage form of oral capsule, limit the performance of its vivo biodistribution availability and antitumor curative effect.It would therefore be highly desirable to solves this The solubility problem of class compound.(2) 7-chloro-4-oxo-quinoline is anti-to S180 sarcomas and the bearing mouse model of ehrlich carcinoma solid type swollen at present Knurl tumour inhibiting rate is only 30% or so, and its antitumor activity has much room for improvement.
Therefore be necessary using 7-chloro-4-oxo-quinoline as primer, the derivative with new biological activity feature is found, in the hope of obtaining New anti-cancer drug better than active compound thing supplies clinical practice.
The content of the invention
Present need exist for finding the new 7-chloro-4-oxo-quinoline class compound with antitumor activity for clinical practice.The present invention It was found that the antitumor activity with desirable with the compound shown in formula I.The present invention is accomplished based on this discovery.
First aspect present invention is provided with compounds of Formula I：
And its pharmaceutically acceptable salt, solvate, prodrug, wherein
R1Selected from hydrogen ,-C1-6Alkyl ,-C2-6Alkenyl ,-C2-6Alkynyl ,-C1-6Alkyl-phenyl, wherein described alkyl, alkene Base, alkynyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl ,-C1-6Alkoxy, phenyl substitution；
R3Selected from hydrogen ,-CONHR31、-COOR32, wherein the R31And R32It is each independently selected from-C1-6Alkyl and-C1-6Alkyl Amino, wherein the amino is optionally by 1~2-C1-6Alkyl substitutes；
R7Selected from halogen ,-C1-6Alkoxy,
Compound according to a first aspect of the present invention, wherein R1Selected from hydrogen ,-C1-6Alkyl ,-C2-6Alkenyl ,-C1-6Alkyl-benzene Base, wherein described alkyl, alkenyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl ,-C1-6Alkoxy.
Compound according to a first aspect of the present invention, wherein R1Selected from hydrogen ,-C1-6Alkyl ,-C2-6Alkenyl ,-C1-6Alkyl-benzene Base.
Compound according to a first aspect of the present invention, wherein R1Selected from hydrogen, methyl, ethyl, propyl group, isopropyl, pi-allyl, Acrylic, benzyl, phenylpropyl, normal-butyl.
Compound according to a first aspect of the present invention, wherein R3Selected from hydrogen ,-CONHR31、-COOR32, wherein the R31With R32It is each independently selected from-C1-4Alkyl and-C1-4Alkyl amino, wherein the amino is optionally by 1~2-C1-4Alkyl substitutes.
Compound according to a first aspect of the present invention, wherein R3Selected from hydrogen ,-COO-C1-4Alkyl ,-CONH-C1-4Alkyl ,- CONH-C1-4Alkyl-NH-C1-4Alkyl ,-CONH-C1-4Alkyl-N (C1-4Alkyl)2。
Compound according to a first aspect of the present invention, wherein R3Selected from hydrogen ,-COOCH2CH3、-CONH-(CH2)2-N (C2H5)2、-CONH-(CH2)3-N(C2H5)2、-CONH-(CH2)3-NH2。
Compound according to a first aspect of the present invention, wherein R7Selected from halogen ,-C1-4Alkoxy,
Compound according to a first aspect of the present invention, wherein R7Selected from fluorine, chlorine, bromine, methoxyl group,
Compound according to a first aspect of the present invention, wherein R1And R3It is asynchronously hydrogen.
Compound according to a first aspect of the present invention, its exclusion condition are：R1And R3It is simultaneously hydrogen, and R7For halogen.
Compound according to a first aspect of the present invention, it is selected from following compound：
The fluoro- 1- methyl -4- oxo-quinolines of 7-,
The chloro- 1- methyl -4- oxo-quinolines of 7-,
The bromo- 1- methyl -4- oxo-quinolines of 7-,
7- methoxyl group -1- methyl -4- oxo-quinolines,
The chloro- 1- isopropyls -4- oxo-quinolines of 7-,
The chloro- 4- oxo-quinolines of 1- pi-allyls -7,
The chloro- 4- oxo-quinolines of 1- benzyls -7-,
The chloro- 1- of 7- (3- phenylpropyls) -4- oxo-quinolines,
The bromo- 4- oxo-quinolines of 1- benzyls -7-,
7- morpholinyls -4 (1H) Oxoquinoline,
1- methyl -7- (4- methylpiperazine-1-yls) -4- oxo-quinolines,
1- benzyl -7- morpholinyl -4- oxo-quinolines,
(1H)-Oxoquinoline -3- formamides of N- (3- (diethylamino) propyl group) -7- fluoro- 4,
The chloro- N- of 7- (3- (diethylamino) propyl group) -4 (1H)-Oxoquinoline -3- formamides,
The bromo- N- of 7- (3- (diethylamino) propyl group) -4 (1H)-Oxoquinoline -3- formamides,
N- (3- diethylaminos) propyl group -7- methoxyl groups -4- (1H)-Oxoquinoline -3- formamides,
The chloro- 1- methyl -4- oxo-quinolines -3- carboxylates of ethyl 7-,
The chloro- 1- ethyls -4- oxo-quinolines -3- carboxylates of ethyl 7-,
The chloro- 4- oxo-quinolines -3- carboxylates of ethyl 1- pi-allyls -7-,
The chloro- 4- oxo-quinolines -3- carboxylates of ethyl 1- butyl -7-,
The chloro- 4- oxo-quinolines -3- carboxylates of ethyl 1- benzyls -7-,
The chloro- 1- of ethyl 7- (3- phenylpropyls) -4- oxo-quinoline -3- carboxylates,
The chloro- N- of 7- [2- (diethylamino) ethyl] -1- methyl -4- oxo-quinoline -3- formamides,
The chloro- N- of 7- [3- (diethylamino) propyl group] -1- methyl -4- oxo-quinoline -3- formamides,
The chloro- N- of 7- [2- (diethylamino) ethyl] -1- ethyl -4- oxo-quinoline -3- formamides,
The chloro- N- of 7- [2- (diethylamino) propyl group] -1- ethyl -4- oxo-quinoline -3- formamides,
The chloro- N- of 1- pi-allyls -7- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formamides,
The chloro- N- of 1- pi-allyls -7- [3- (diethylamino) propyl group] -4- Oxoquinoline -3- formamides,
The chloro- N- of 1- butyl -7- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formamides,
The chloro- N- of 1- butyl -7- [3- (diethylamino) propyl group] -4- oxo-quinoline -3- formamides,
The chloro- N- of 1- benzyls -7- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formamides,
The chloro- N- of 1- benzyls -7- [2- (diethylamino) propyl group] -4- oxo-quinoline -3- formamides,
The chloro- N- of 7- [3- (diethylamino) propyl group] -1- (3- phenylpropyls) -4- oxo-quinoline -3- formamides,
The chloro- 1- ethyls -4- oxo-quinolines -3- formamides of N- (3- aminopropyls) -7-,
The chloro- 4- oxo-quinolines -3- formamides of 1- pi-allyls-N- (3- aminopropyls) -7-,
The chloro- 4- oxo-quinolines -3- formamides of N- (3- aminopropyls) -1- butyl -7-,
The chloro- 1- benzyls -4- oxo-quinolines -3- formamides of N- (3- aminopropyls) -7-,
N- (3- aminopropyls) -7- chloro- 1- (3- phenylpropyls) -4- oxo-quinoline -3- formamides,
And their pharmaceutically acceptable salt, solvate, prodrug.
Second aspect of the present invention is related to compound of formula I described in any one of first aspect present invention, its dynamic isomer, disappeared Rotation body or optical isomer, its pharmaceutical salts or solvate are preparing the purposes in can be used for preventing or treating the medicine of tumour.
Fourth aspect present invention provides a kind of pharmaceutical composition, wherein the formula containing at least one first aspect present invention I and Formula II described below, formula III compound or its pharmaceutically acceptable salt, solvate, prodrug, and optionally Pharmaceutical carrier or excipient.According in this respect, it is used as the invention further relates to described pharmaceutical composition and is used to prevent or treat swollen Application in the medicine of the diseases such as knurl.
Fifth aspect present invention provide prevention and/or treatment tumour method, this method include to have this need by Examination person gives the compound of formula I and Formula II described below, formula III compound of the first aspect of prevention and/or therapeutically effective amount Or its pharmaceutically acceptable salt, solvate, prodrug.
Sixth aspect present invention provides the compound of formula I for preparing first aspect or its pharmaceutically acceptable salt, solvent close The method of thing, prodrug, it comprises the following steps：
A) formula is madeThe reaction of compound and ethoxy methylene diethyl malonate (such as in heating condition Under, such as at 80~120 DEG C), obtain following formula: compound：
B) compound obtained by step a) is added in suitable solvent (such as diphenyl ether), in a heated condition (such as Under solvent boiling or counterflow condition) mixture is reacted, reaction adds petroleum ether, isolated following formula after terminating Compound：
C) to aqueous alkali (such as sodium hydrate aqueous solution, such as 5~20% hydrogen will be added in compound obtained by step b) Aqueous solution of sodium oxide), heating (such as backflow) reaction, reaction terminate after with acid (such as hydrochloric acid, such as concentrated hydrochloric acid) acidifying, obtain Following formula: compound
D) compound obtained by step c) is added in suitable solvent (such as diphenyl ether), in a heated condition (such as Reacted mixture under reflux conditions), reaction adds petroleum ether after terminating, the 7- substitutions shown in isolated following formula- 4- (1H)-oxoquinoline compound：
E) make compound obtained by step d) being dissolved in suitable solvent (such as DMF), add NaH, then add halogen For alkane R1- Y makes to be reacted, and obtains R3For the following formula: compound of the present invention of hydrogen：
Wherein,
X represents halogen or-C1-4Alkoxy,
Y represents halogen,
R1Selected from-C1-6Alkyl ,-C2-6Alkenyl ,-C1-6Alkyl-phenyl, such as particularly R1Selected from selected from methyl, ethyl, third Base, isopropyl, pi-allyl, acrylic, benzyl, phenylpropyl, normal-butyl.
Sixth aspect present invention additionally provides the compound of formula I or its pharmaceutically acceptable salt, solvent for preparing first aspect The method of compound, prodrug, it comprises the following steps：
A) in suitable solution (such as Isosorbide-5-Nitrae-dioxane), in KN [Si (CH3)3]2In the presence of, make formulaCompound and morpholine or N methyl piperazine reaction (such as it is lower in a heated condition react, such as flowing back Under the conditions of react), obtain following formula: compound of the present invention：Wherein R1For hydrogen or-C1-6Alkyl such as methyl, R7ForOrOr
B) in suitable solution (such as DMSO), in the presence of cuprous iodide, L-PROLINE, tripotassium phosphate, formula is madeCompound and morpholine reaction (such as lower reaction, such as react under reflux conditions in a heated condition), are obtained To following formula: compound of the present invention：Wherein R1For-C1-6Alkyl-phenyl such as benzyl, R7For
Sixth aspect present invention additionally provides the compound of formula I or its pharmaceutically acceptable salt, solvent for preparing first aspect The method of compound, prodrug, it comprises the following steps：
A) ethyl 7- shown in following formula is made to substitute -4 (1H)-Oxoquinoline-3-carboxylic acid esters
Mixed with 3- (diethylamino) propylamine, heating (such as at 120~180 DEG C) makes reaction, obtains following formula of the present invention Compound：
Wherein X is halogen or-C1-6Alkoxy, such as X are fluorine, chlorine, bromine or methoxyl group.
Sixth aspect present invention additionally provides the compound of formula I or its pharmaceutically acceptable salt, solvent for preparing first aspect The method of compound, prodrug, it comprises the following steps：
A) formula is madeCompound in suitable solvent (such as DMF), in the presence of NaH with Formula R1The halogenated alkane that-Y is represented is reacted, and obtains following formula: compound of the present invention：
And optionally further,
B) compound obtained by step a) and formula H are made2N-(CH2)n-NH2、H2N-(CH2)n-N(C2H5)2The diamines of expression mixes Close, heating (such as at 120~180 DEG C) makes reaction, obtains following formula: compound of the present invention：
Wherein
Y represents halogen,
N is 2 or 3,
R1Selected from-C1-6Alkyl ,-C2-6Alkenyl ,-C1-6Alkyl-phenyl, such as particularly R1Selected from selected from methyl, ethyl, third Base, isopropyl, pi-allyl, acrylic, benzyl, phenylpropyl, normal-butyl.
More than in the inventive method of the 6th aspect, wherein the definition of each symbol such as any one of first aspect present invention formula Described in I.
Seventh aspect present invention provides a kind of compound, and it is with compound shown in Formula Il
And its pharmaceutically acceptable salt, solvate, prodrug, wherein
R4Selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C1-6Alkyl (such as methyl, ethyl, propyl group, isopropyl, positive fourth Base) ,-C1-6Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy) ,-NH-C1-6Alkyl-N (C1-4 Alkyl)2；
R7Selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C1-6Alkyl (such as methyl, ethyl, propyl group, isopropyl, positive fourth Base) ,-C1-6Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy) ,-C1-6Alkenyl epoxide (such as Ethyleneoxy, propenyloxy group, butenyloxy) ,-C1-6Alkyl-phenyl ,-C1-6Alkyl-halo (such as chlorine, fluorine, bromine, iodo) benzene Base.
Compound according to a seventh aspect of the present invention, it is selected from：
4,7- dichloroquinolines,
The chloro- 7- methoxy quinolines of 4-,
7- chloro-4-methoxy quinoline,
The chloro- 4- ethoxyquinolines of 7-,
The chloro- 4- isopropoxies quinoline of 7-,
4,7- dimethoxy-quinolines,
4- ethyoxyl -7- methoxy quinolines,
The chloro- 7- oxyquinolines of 4-,
The chloro- 7- ethoxyquinolines of 4-,
The chloro- 7- n-butoxies quinoline of 4-,
The chloro- 7- positive hexyloxies quinoline of 4-,
The chloro- 7- allyloxys quinoline of 4-,
The chloro- 7- isopropoxies quinoline of 4-,
The chloro- 7- isobutoxies quinoline of 4-,
The chloro- 7- benyloxyquinolines of 4-,
The chloro- 7- of 4- (4- fluorine benzyloxy) quinoline,
The chloro- 7- of 4- (3- benzene ethyoxyl) quinoline,
The chloro- 7- of 4- (3- phenylpropyl alcohols epoxide) quinoline,
N1- (7- ethoxyquinoline -4- bases)-N2,N2- diethyl ethane -1,2- diamines,
N1,N1- diethyl-N2- (7- hexyloxies quinolyl-4) ethane -1,2- diamines,
N1- (7- allyloxys quinolyl-4)-N2,N2- diethyl ethane -1,2- diamines,
N1,N1- diethyl-N2- (7- isopropoxies quinolyl-4) ethane -1,2- diamines,
N1- (7- benyloxyquinoline -4- bases)-N2,N2- diethyl ethane -1,2- diamines,
N1,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) ethane -1,2- diamines,
N1- (7- ethoxyquinoline -4- bases)-N2,N2- diethyl propane -1,2- diamines,
N1- (7- allyloxys quinolyl-4)-N2,N2- diethyl propane -1,2- diamines,
N1,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) propane -1,2- diamines,
And its pharmaceutically acceptable salt, solvate, prodrug.
Eighth aspect present invention provides a kind of compound, and it is compound shown in following formula III
And its pharmaceutically acceptable salt, solvate, prodrug, wherein
Y is 1 to 4 group for being selected from halogen, such as Y is 1-2 individual selected from fluorine, chlorine, bromine, the group of iodine, such as Y is 2 Chlorine.
Compound according to a eighth aspect of the present invention, it is selected from：
5,8- bis- chloro- 4- (1H)-Oxoquinolines, and
6,8- bis- chloro- 4- (1H)-Oxoquinolines,
And its pharmaceutically acceptable salt, solvate, prodrug.
Feature possessed by any one of either side or the either side of the present invention is equally applicable to other either sides Or any one of other either sides, as long as they will not be conflicting, certainly in mutual where applicable, if necessary may be used Individual features are made with appropriate modification.In the present invention, for example, when referring to " any one of first aspect present invention ", it is somebody's turn to do " any one " Refer to any son aspect of first aspect present invention；When other side refers in a similar manner, also with identical meanings.
It is further described to various aspects of the present invention with feature below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary When offering expressed implication and the inconsistent present invention, it is defined by the statement of the present invention.In addition, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention The implication stated is defined.
Make group definition, composition explanation, usage description of use etc. below for compound of formula I, if will not produce Contradiction, then these it is descriptive explanation may be equally applicable for Formula II compound and formula III compound.
Term " halogen ", " halogen ", " Hal " or " halo " employed in the present invention refers to fluorine, chlorine, bromine and iodine.
Term " alkyl ", " alkenyl " and " alkynyl " employed in the present invention has general sense well known in the art, They are the hydrocarbyl groups of straight or branched, such as, but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, uncle Butyl, pi-allyl, acrylic, propinyl etc., and described " alkyl ", " alkenyl " and " alkynyl " may be collectively referred to as " alkyl " Or " chain alkylene ".In yet other embodiments, described " alkyl " refers to that alkyl includes alkyl group and cycloalkanes Base, particularly alkyl group such as C1-C6 alkyl.
As used herein, term " aryl " is such as, but not limited to phenyl, naphthyl.
As used herein, phrase " substituted or unsubstituted C1-C6 alkyl ", which refers to have, specifies number taking for carbon atom Generation or unsubstituted alkyl group, the example include but is not limited to：Methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, penta Base, neopentyl, hexyl.
The present invention relates to a series of compounds for including quinazolone ring, for convenience of identifying, the quinazolone ring and its annular atom Numbering can represent in the following orderWherein theheterocyclic nitrogen atom is 1, and the ring carbon at oxo base is 4.
In the present invention, group " C1-C6Alkyl " and " C1-6The two has identical meanings to alkyl ", represents there is 1-6 The straight or branched alkyl of carbon atom.Other situations can also make similar understanding.
In the present invention, group " C1-6Alkyl " can for example be selected from C1-5Alkyl, C1-4Alkyl.Similarly ,-C1-6Alkoxy Such as C can be selected from1-5Alkoxy, C1-4Alkoxy ,-C2-6Alkenyl can for example be selected from C2-5Alkenyl, C2-4Alkenyl ,-C2-6Alkynyl Such as C can be selected from2-5Alkynyl, C2-4Alkynyl.
In the method for synthetic compound of formula i of the present invention, the various raw material for reacting used are those skilled in the art's roots It can be prepared according to existing knowledge, or can be by made from method known to document, or business can be passed through What industry was bought.Intermediate used, raw material, reagent, reaction condition etc. can be according to this area skills in above reaction scheme The existing knowledge of art personnel can make what is suitably changed.Or those skilled in the art can also be square according to a second aspect of the present invention The not specifically enumerated other compound of formula I of the method synthesis present invention.
According to the present invention, the pharmaceutical salts of compound of formula I can be acid-addition salts or the salt formed with alkali.Acid-addition salts are illustrated Say it can is that inorganic acid salt is such as, but not limited to hydrochloride, sulfate, phosphate, hydrobromate；Or acylate is for example but not Be limited to acetate, oxalates, sal limonis, gluconate, succinate, tartrate, tosilate, mesylate, Benzoate, lactate and maleate；Compound of formula I is said with the citing of alkali forming salt can be alkali metal salt for example but be not limited to Lithium, sodium and sylvite；Alkali salt for example but is not limited to calcium and magnesium salts；Organic alkali salt is such as, but not limited to diethanolamine salt and courage Alkali salt etc.；Or chiral alkali salt is such as, but not limited to alkyl phenyl amine salt.
The solvate of the compound of the present invention can be hydrate or comprising other recrystallisation solvents such as alcohols such as second Alcohol.
According to the present invention, compound of formula I may have cis/trans isomers, and the present invention relates to cis form and trans forms And the mixture of these forms.If desired, the preparation of single stereoisomers can split mixture according to conventional methods, or Prepared for example, by Stereo-selective synthesis.If there is motor-driven hydrogen atom, the present invention also relates to the tautomerism of compound of formula I Form.
Therefore the present invention further relates at least one compound of formula I containing the effective dose as active ingredient, or its medicine With salt and/or its stereoisomer and the pharmaceutical composition of customary pharmaceutical excipients or assistant agent.Usual drug regimen of the present invention Thing contains 0.1-90 weight % compound of formula I and/or its physiologically acceptable salt.Pharmaceutical composition can be according to this area It is prepared by the method known.When for this purpose, if it is desired, can consolidate compound of formula I and/or stereoisomer with one or more Body or liquid pharmaceutical excipients and/or assistant agent combine, and being made can be as the appropriate administration form or dosage form of people.
The compound of formula I of the present invention can be administered in a unit containing its pharmaceutical composition, and method of administration can For enteron aisle or non-bowel, in such as oral, muscle, subcutaneous, knurl, nasal cavity, oral mucosa, skin, peritonaeum or rectum.Form of administration Such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, liposome, transdermal agent, Buccal tablet, suppository, freeze drying powder injection, injection etc..Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulates to Medicine system.In order to which unit dosage forms for administration is made into tablet, various carriers well known in the art can be widely used.On carrier Example is, such as diluent and absorbent, as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, Urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, second Alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, purple Glue, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, such as dry starch, alginate, agar powder, brown Algae starch, sodium acid carbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methyl are fine Tie up element, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；Absorption enhancement Agent, such as quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, for example, talcum powder, silica, cornstarch, stearate, Boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film coating Piece, enteric coated tablets, or double-layer tablets and multilayer tablet.In order to which administration unit is made into pill, can widely use known in this field Various carriers.Example on carrier is, such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenation Vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive for example Arabic gum, bassora gum, gelatin, Ethanol, honey, liquid sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, Methylcellulose, ethyl cellulose etc..In order to which administration unit is made into suppository, various loads well known in the art can be widely used Body.Example on carrier is, such as the ester of polyethylene glycol, lecithin, cocoa butter, higher alcohol, higher alcohol, gelatin, semi-synthetic Glyceride etc..In order to which administration unit is made into capsule, by active ingredient compound of formula I or its stereoisomer with it is above-mentioned various Carrier is mixed, and thus obtained mixture is placed in hard obviously capsule or soft capsule.Also can be by active ingredient Formulas I chemical combination Microcapsules is made in thing or its stereoisomer, is suspended in aqueous medium and forms supensoid agent, also can be fitted into hard shell capsules or be made Injection application., can be with such as solution, emulsion, freeze drying powder injection and supensoid agent in order to which administration unit is made into injection preparation Using all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1,3-PD, the different tristearin of ethoxylation Alcohol, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can be to note Penetrate with appropriate sodium chloride, glucose or glycerine is added in preparation, further, it is also possible to add conventional cosolvent, buffer, pH Conditioning agent etc..
In addition, if desired, can also be added into pharmaceutical preparation colouring agent, preservative, spices, flavouring, sweetener or Other materials.
Formula I, or the dosage of its isomers depend on many factors, such as to be prevented or treated Sex, age, body weight and the individual reaction of the property and the order of severity of disease, patient or animal, particular compound used, give Medicine approach and administration number of times etc..Above-mentioned dosage with ingle dose form or can be divided into several, such as two, three or four dosage forms Administration.
Term " composition " used herein means to include the product of each specified composition comprising specified amount, and directly or Any product caused by combination from each specified composition of specified amount indirectly.
It is horizontal that the actual dose of each active component in pharmaceutical composition of the present invention can be changed, so as to the reactive compound of gained Amount effectively can obtain required therapeutic response for specific patient, composition and administering mode.Dosage level must be according to materialization Activity, method of administration, the order of severity for treating the patient's condition and the patient's condition of patient to be treated and medical history of compound is selected. But the way of this area is, the dosage of compound is since less than the level for obtaining required therapeutic effect and requiring, gradually Incremental dose, until obtaining required effect.
The compound of the present invention can be used for preparing antineoplastic.The tumour includes but is not limited to melanoma, stomach Cancer, lung cancer, breast cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical carcinoma, oophoroma, cancer of pancreas, prostate cancer, colon cancer, bladder The malignant tumours such as cancer, head and neck neoplasm, nasopharyngeal carcinoma, cutaneum carcinoma and leukaemia.Described stomach cancer includes sdenocarcinoma of stomach；Described lung cancer Including adenocarcinoma of lung；Described colon cancer includes adenocarcinoma of colon；Described oophoroma includes adenocarcinoma ovaries；Described kidney includes kidney Clear cell adenocarcinoma；Leukaemia includes ALL, chronic leukemia, specific type leukaemia.
When for above-mentioned treatment and/or prevention or other treatment and/or prevention when, treatment and/or prevention effective dose one Kind the compounds of this invention can be applied in a pure form, or by pharmaceutically acceptable ester or prodrug forms (in the form of it these be present In the case of) application.Or the compound can be subjected to figuration to contain the purpose compound with one or more medicines The pharmaceutical composition administration of agent.The compounds of this invention of word " prevention and/or therapeutically effective amount " refers to suitable for any medical science The compound of the sufficient amount of the reasonable effect of prevention and/or treatment/Hazard ratio treatment obstacle.It is to be understood that chemical combination of the present invention Total consumption per day of thing and composition must be maked decision by attending physician in reliable medical judgment scope.For any specific Patient, specific treatment effective dose level must be depending on many factors, and the factor includes treated obstacle and the barrier The order of severity hindered；The activity of used particular compound；Used concrete composition；It is age of patient, body weight, general Health status, sex and diet；Administration time, method of administration and the excretion rate of used particular compound；When treatment continues Between；It is applied in combination with used particular compound or medicine used at the same time；And similar factor known to medical field.Example Such as, the way of this area is that the dosage of compound gradually increases since less than the level for obtaining required therapeutic effect and requiring Add dosage, until obtaining required effect.It is, in general, that formula I is used for the dosage of mammal particularly people Can between 0.001~1000mg/kg body weight/days, such as between 0.01~100mg/kg body weight/days, such as between 0.01~ 10mg/kg body weight/days.
Embodiment
The present invention can be further illustrated by the following example, but these examples of implementation are not meant that to the present invention's Any restrictions.
Following synthetic route 1 depicts some intermediates for preparing the compounds of this invention and some compounds of the present invention Conventional method.
Synthetic route 1
Compound 6a-d General Synthetic Procedures：
(1) Xi Fushi alkali 3a-d synthesis：
Aniline 1a-d (100mmol) and ethoxy methylene diethyl malonate 2 (23.3g, 108mmol) between will be corresponding Mixing, it is stirred at room temperature to solution and clarifies.Then above-mentioned reaction mixture is reacted 2 hours in 100 DEG C of heating stirrings, reacted Finish, it is not necessary to post processing and purifying, reaction mixture (i.e. Xi Fushi alkali 3a-d) is directly added into next step reaction bulb.
(2) Oxoquinoline-3-carboxylic acid ester 4a-d synthesis
Diphenyl ether (100ml) is added in 250ml round-bottomed flask, be heated with stirring to boiling.Then while hot by previous step Reaction obtains Xi Fushi alkali 3a-d and is added drop-wise in the hexichol ethereal solution of boiling.Finish, continue heating reflux reaction, about 15 minutes left sides Right bottle wall separates out white solid, and about 45 minutes or so, solid was full of whole bottle solution and gradually turns yellow.Stop reaction, cooling reaction Liquid adds 60-90 DEG C of petroleum ether (100ml) into reaction bulb, after stirring, filtering, petroleum ether, obtained white to room temperature Solid, as intermediate Oxoquinoline-3-carboxylic acid ester 4a-d.
(the 1H)-Oxoquinoline-3-carboxylic acid esters (4a) of ethyl 7- fluoro- 4
With m-fluoroaniline 1a (100mmol) for raw material, white solid (16.9g, 72%) is obtained
(the 1H)-Oxoquinoline-3-carboxylic acid esters (4b) of ethyl 7- chloro- 4
With m-chloroaniline 1b (100mmol) for raw material, white solid (19.6g, 78%) is obtained
(the 1H)-Oxoquinoline-3-carboxylic acid esters (4c) of ethyl 7- bromo- 4
With m-bromoaniline 1c (100mmol) for raw material, white solid (22.2g, 75%) is obtained
(the 1H)-Oxoquinoline-3-carboxylic acid ester (4d) of ethyl 7- methoxyl groups -4
With 3- aminoanisoles 1d (100mmol) for raw material, white solid (16.3g, 66%) is obtained
(3) Oxoquinoline-3-carboxylic acid 5a-d synthesis
Product Oxoquinoline-3-carboxylic acid ester 4a-d (20mmol) obtained in the previous step is added in round-bottomed flask, then added Enter 10%NaOH solution (150ml), be heated to reflux under stirring condition 1 hour.Reaction solution is cooled down to room temperature, it is dilute to add 500ml water To release reaction solution and adjust pH to 6.0 with concentrated hydrochloric acid, separate out faint yellow solid, filtering, water fully washs, and dries, obtains white solid, As intermediate Oxoquinoline-3-carboxylic acid 5a-d.
(the 1H)-Oxoquinoline-3-carboxylic acids (5a) of 7- fluoro- 4:Obtain white solid (4.1g, 98%)
(the 1H)-Oxoquinoline-3-carboxylic acids (5b) of 7- chloro- 4:Obtain white solid (4.3g, 97%)
(the 1H)-Oxoquinoline-3-carboxylic acids (5c) of 7- bromo- 4:Obtain white solid (5.2g, 98%)
7- methoxyl groups -4 (1H)-Oxoquinoline-3-carboxylic acid (5d):Obtain white solid (4.2g, 96%)
(4) 7- substitutions -4- (1H)-Oxoquinoline 6a-d synthesis
Corresponding intermediate Oxoquinoline-3-carboxylic acid 5a-d (16.0g) and the diphenyl ether (100ml) that previous step is reacted to obtain Mixing, heating reflux reaction.Carboxylic acid does not dissolve first.As temperature raises, insoluble solids are gradually decreased and produced with a large amount of bubbles It is raw.Heating reflux reaction about 30 minutes, bubble-free produce, and stop reaction, and cooling reaction solution has pale solid analysis to room temperature Go out.60-90 DEG C of petroleum ether (100ml) is added, is filtered after stirring, obtains white solid.
(the 1H)-Oxoquinolines (6a) of 7- fluoro- 4
Obtain white solid (1.5g, 92%).ESI-MS m/z 164[M+H]+.1H NMR(300MHz,DMSO-d6):δ 11.75 (1H, s), 8.07-8.13 (1H, m), 7.88 (1H, d, J=7.2Hz), 7.23-7.27 (1H, m), 7.13-7.17 (1H, M), 6.02 (1H, d, J=7.2Hz)
(the 1H)-Oxoquinolines (6b) of 7- chloro- 4
Obtain white solid (1.5g, 86%).ESI-MS m/z 180[M+H]+.1H NMR(300MHz,DMSO-d6):δ 11.75 (1H, s), 8.03 (1H, d, J=8.7Hz), 7.88 (1H, d, J=7.2Hz), 7.55 (1H, d, J=2.1Hz), 7.28 (1H, dd, J=8.7Hz, J=2.1Hz), 6.02 (1H, d, J=7.2Hz)
(the 1H)-Oxoquinolines (6c) of 7- bromo- 4
Obtain white solid (2.0g, 88%).ESI-MS m/z 224[M]+.1H NMR(300MHz,DMSO-d6):δ11.75 (1H, s), 7.95 (1H, d, J=8.7Hz), 7.88 (1H, d, J=7.5Hz), 7.71 (1H, d, J=1.8Hz), 7.41 (1H, Dd, J=8.7Hz, J=2.1Hz), 6.02 (1H, d, J=7.5Hz)13C NMR(75MHz,CDCl3)δ177.1,141.6, 140.6,128.0,126.8,125.7,125.2,121.1,110.0.
7- methoxyl groups -4 (1H)-Oxoquinoline (6d)
Obtain white solid (1.6g, 86%).ESI-MS m/z 176[M+H]+.1H NMR(300MHz,DMSO-d6):δ 11.63 (1H, s), 7.93 (1H, d, J=8.7Hz), 7.76 (1H, d, J=7.5Hz), 6.91 (1H, d, J=2.4Hz), 6.88 (1H, dd, J=8.7Hz, J=2.4Hz) 5.91 (1H, d, J=7.5Hz), 3.83 (3H, s)
The compounds of this invention 7a to 7i General Synthetic Procedures：
Substitute -4- (1H)-Oxoquinoline (10mmol) to be dissolved in DMF (60ml) 7-, be stirred at room temperature to clarification, add 60% NaH (0.8g, 20mmol), be stirred at room temperature 5 minutes, add corresponding alkyl halide (15-25mmol), be stirred at room temperature reaction, TLC with Track detects.Reaction is finished, and reaction mixture is poured into water, and ethyl acetate extraction (150ml × 3), merges organic phase, is washed, Saturated salt is washed.Organic phase is acidified (pH 1~2) with concentrated hydrochloric acid, is concentrated under reduced pressure near dry, absolute ethyl alcohol band water 2 times, residual Thing acetone recrystallization.Filtering, obtains yellow solid.Above-mentioned yellow solid is dissolved in water, sodium acid carbonate alkalization, ethyl acetate extracts, Anhydrous sodium sulfate drying, filtering, filtrate decompression are concentrated to dryness, and residue ether or ether/petroleum ether recrystallization, produce target production Thing 7a-i.Wherein
Embodiment 1：Prepare the fluoro- 1- methyl -4- oxo-quinolines (compound 7a) of 7-
With (the 1H)-Oxoquinoline 6a (5.0mmol) of 7- fluoro- 4 and iodomethane (7.5mmol) for raw material.Obtain white solid (0.86g, 86%).ESI-MSm/z 178[M+H]+.1H NMR(300MHz,CDCl3):δ8.40-8.45(1H,m),7.47 (1H, d, J=7.5Hz), 7.00-7.11 (2H, m), 6.20 (1H, d, J=7.5Hz), 3.74 (3H, s)
Embodiment 2：Prepare the chloro- 1- methyl -4- oxo-quinolines (compound 7b) of 7-
With (the 1H)-Oxoquinoline 6b (5.0mmol) of 7- chloro- 4 and iodomethane (7.5mmol) for raw material.Obtain white solid (0.67g, 69%), mp233-234 DEG C.ESI-MS m/z 194[M+H]+.1H NMR(300MHz,CDCl3):δ8.30(1H,d, ), J=8.7Hz 7.43 (1H, d, J=7.8Hz), 7.34 (1H, d, J=1.8Hz), 7.28 (1H, dd, J=8.7Hz, J= 1.8Hz), 6.18 (1H, d, J=7.8Hz), 3.74 (3H, s)13CNMR(75MHz,CDCl3) δ 177.6 (C=O), 144.1, 141.4,138.8,128.8,125.5,124.5,115.4,110.8,41.0.
Embodiment 3：Prepare the bromo- 1- methyl -4- oxo-quinolines (compound 7c) of 7-
With (the 1H)-Oxoquinoline 6c (5.0mmol) of 7- bromo- 4 and iodomethane (7.5mmol) for raw material.Obtain white solid (1.0g, 88%).ESI-MSm/z 239[M+H]+.1H NMR(300MHz,CDCl3):δ 8.27 (1H, d, J=8.7Hz), 7.44-7.54 (3H, m), 6.23 (1H, d, J=7.8Hz), 3.76 (3H, s)13C NMR(75MHz,CDCl3)δ176.5, 146.1,128.5,128.4,127.1,126.6,126.0,120.0,109.9,40.8.
Embodiment 4：Prepare 7- methoxyl group -1- methyl -4- oxo-quinolines (compound 7d)
With 7- methoxyl groups -4 (1H)-Oxoquinoline 6d (5.0mmol) and iodomethane (7.5mmol) for raw material.Obtain white solid Body (0.76g, 80%).Mp 179-180℃.ESI-MS m/z 190[M+H]+.1H NMR(300MHz,DMSO-d6):δ8.31 (1H, d, J=8.7Hz), 7.40 (1H, d, J=7.5Hz), 6.94 (1H, dd, J=8.7Hz, J=1.8Hz), 6.66 (1H, s), 6.15 (1H, d, J=7.5Hz), 3.91 (3H, s), 3.71 (3H, s)13CNMR(75MHz,CDCl3)δ176.4,162.8, 145.4,142.9,128.0,121.2,113.4,109.1,99.2,56.4,40.9.
Embodiment 5：Prepare the chloro- 1- isopropyls -4- oxo-quinolines (compound 7e) of 7-
With (the 1H)-Oxoquinoline 6b (5.0mmol) of 7- chloro- 4 and 2- N-Propyl Bromides (20mmol) for raw material, white solid is obtained (0.75g, 68%).ESI-MSm/z 222[M+H]+.1H NMR(300MHz,CDCl3):δ 9.08 (1H, d, J=6.9Hz), 8.28-8.32 (2H, m), 7.82 (1H, dd, J=9.0Hz, J=2.1Hz), 7.54 (1H, d, J=6.9Hz), 5.20-5.32 (1H,m),1.49(3H,s),1.47(3H,s).13C NMR(75MHz,CDCl3) δ 167.5 (C=O), 147.9,139.8, 139.5,129.7,125.9,119.9,119.8,104.2,76.1,22.0.
Embodiment 6：Prepare -7 chloro- 4- oxo-quinolines (compound 7f) of 1- pi-allyls
With (the 1H)-Oxoquinoline 6b (5.0mmol) of 7- chloro- 4 and allyl bromide, bromoallylene (7.5mmol) for raw material, white solid is obtained (0.9g, 82%).ESI-MSm/z 220[M+H]+.1H NMR(300MHz,CDCl3):δ 8.32 (1H, d, J=8.4Hz), 7.46 (1H, d, J=7.8Hz), 7.26-7.32 (2H, m), 6.23 (1H, d, J=7.8Hz), 5.90-6.03 (1H, m), 5.09-5.34 (2H,m),4.64-4.67(2H,m).13C NMR(75MHz,CDCl3) δ 177.5 (C=O), 143.6,140.8,138.6, 130.9,128.7,125.6,124.4,119.0,115.8,111.0,55.2.
Embodiment 7：Prepare the chloro- 4- oxo-quinolines (compound 7g) of 1- benzyls -7-
With (the 1H)-Oxoquinoline 6b (5.0mmol) of 7- chloro- 4 and cylite (7.5mmol) for raw material, white solid is obtained (0.95g, 70%).Mp202-203℃.ESI-MS m/z 270[M+H]+.1H NMR(300MHz,CDCl3):δ8.34(1H,d, J=9.0Hz), 7.58 (1H, d, J=7.8Hz), 7.25-7.36 (5H, m), 7.12 (2H, d, J=6.9Hz), 6.30 (1H, d, J =7.8Hz), 5.27 (2H, s)13C NMR(75MHz,CDCl3) δ 177.6 (C=O), 144.1,141.0,138.7,134.7, 129.5,128.8,128.7,126.3,125.8,124.6,116.0,111.1,56.7.
Embodiment 8：Prepare 7- chloro- 1- (3- phenylpropyls) -4- oxo-quinolines (compound 7h)
With (the 1H)-Oxoquinoline 6b (5.0mmol) of 7- chloro- 4 and 1- (3- bromopropyls) benzene (25mmol) for raw material, yellow is obtained Grease (1.0g, 68%).ESI-MS m/z 298[M+H]+.1H NMR(300MHz,CDCl3):δ 8.35 (1H, d, J= 8.7Hz), 7.40 (1H, d, J=7.8Hz), 7.18-7.34 (7H, m), 6.22 (1H, d, J=7.8Hz), 4.03 (2H, t, J= 7.5Hz), 2.74 (2H, t, J=7.5Hz), 2.16-2.26 (2H, m)13CNMR(75MHz,CDCl3) δ 177.5 (C=O), 143.6,140.5,139.8,138.7,129.0,128.5,126.9,125.8,124.4,115.3,110.8,52.6,32.8, 30.1.
Embodiment 9：Prepare the bromo- 4- oxo-quinolines (compound 7i) of 1- benzyls -7-
With (1H)-Oxoquinoline 6c (5.0mmol) a of 7- bromo- 4 and cylite (7.5mmol) for raw material, white solid is obtained (1.32g, 84%).ESI-MS m/z 315[M+H]+.1H NMR(300MHz,CDCl3):δ 8.29 (1H, d, J=8.7Hz), 7.56 (1H, d, J=7.8Hz), 7.32-7.48 (5H, m), 7.13-7.16 (2H, m), 6.31 (1H, d, J=7.8), 5.26 (2H,s).13C NMR(75MHz,CDCl3)δ177.1,144.0,141.1,134.7,129.5,128.9,128.7,127.3, 126.4,126.2,119.1,111.2,111.1,56.6.
Following synthetic route 2 depicts some intermediates for preparing the compounds of this invention and some compounds of the present invention Conventional method.
Synthetic route 2：
Embodiment 10：The synthesis of 7- morpholinyls -4 (1H)-Oxoquinoline (compound 15)
Isosorbide-5-Nitrae-dioxane (6ml), morpholine (0.21ml, 2.4mmol), KN are sequentially added in 50ml round-bottomed flask [Si(CH3)3]2(the 1H)-Oxoquinoline (0.45g, 2mmol) of (2.64ml, 2.4mmol) and 7- bromo- 4, finishes, is stirred at room temperature 5 points Clock, back flow reaction in subsequent 100 DEG C of oil baths, TLC tracing detections, reaction finish, and cooling reaction solution to room temperature, it is whole to add 20ml water Only react, regulation pH value to 6.0, be concentrated under reduced pressure into dry, absolute ethyl alcohol band water 3 times, residue silica gel column chromatography, dichloromethane： Methanol=10：1, obtain yellow oil (0.16g, 35%).ESI-MS m/z230.8[M+H]+.1H NMR(300MHz,DMSO- d6):δ 11.38 (1H, s), 7.88 (1H, d, J=7.2Hz), 7.69-7.73 (1H, m), 7.02 (1H, dd, J=7.2Hz, 1.2Hz), 6.71 (1H, s), 5.87 (1H, d, J=7.2Hz), 3.73 (4H, t, J=4.5Hz), 3.20 (4H, t, J= 4.5Hz).13CNMR(75MHz,CDCl3)δ177.1,153.8,142.3,139.4,126.6,119.3,113.4,108.9, 100.1,66.7,48.2.
Embodiment 11：The synthesis of 1- methyl -7- (4- methylpiperazine-1-yls) -4- oxo-quinolines (compound 16)
Sequentially added in 50ml round-bottomed flask Isosorbide-5-Nitrae-dioxane (12ml), N methyl piperazine (0.4ml, 3.6mmol)、KN[Si(CH3)3]2(4ml, 3.64mmol) and 7- bromo- 1- methyl -4 (1H)-Oxoquinoline (0.48g, 2mmol), Finish, vacuumize immediately, take out complete, be filled with N immediately2, take out repeatedly 4 times, every time 1 minute.Then reaction mixture is put into 100 DEG C of oil Flowed back in bath about 15 hours, TLC tracing detections.Reaction finishes, cooling reaction solution to room temperature, adds 5ml water terminating reactions, decompression It is concentrated to dryness, methanol dissolving reaction residue, filters off except insoluble matter, filtrate are concentrated to dryness, silica gel column chromatography, dichloromethane： Methanol=30：1 washing, obtains yellow oil (0.16g, 31%).ESI-MS m/z 257.9[M+H]+.1H NMR(300MHz, DMSO-d6):δ 8.25 (1H, d, J=9.0Hz), 7.36 (1H, d, J=7.5Hz), 6.99 (1H, dd, J=9.0Hz, 2.1Hz), 6.49 (1H, d, J=2.1Hz), 6.13 (1H, d, J=7.5Hz), 3.70 (3H, s), 3.38 (4H, t, J=4.8Hz), 2.59 (4H, t, J=4.8Hz), 2.36 (3H, s)13C NMR(75MHz,CDCl3)δ177.1,153.8,142.3,139.4,126.6, 119.3,113.4,108.9,100.1,66.7,48.2.
Embodiment 12：The synthesis of 1- benzyl -7- morpholinyl -4- oxo-quinolines (compound 17)：
The bromo- 1- benzyls -4 (1H) of 7--Oxoquinoline (0.64g, 2mmol), iodine are sequentially added in 50ml round-bottomed flask Change cuprous (0.05g), L-PROLINE (0.05g, 1mmol), tripotassium phosphate (0.42g, 2mmol), morpholine (0.2ml, 1.5mmol) With DMSO (1.5ml), finish, reacted in 90 DEG C of oil baths, TLC tracing detections.Reaction finishes, and adds 0.5ml ammoniacal liquor terminating reactions, 10ml water and 20ml dichloromethane are then added, separates organic phase, aqueous phase dichloromethane is extracted twice, and merges organic phase, is washed, Saturated salt is washed, anhydrous sodium sulfate drying.Filtering, filtrate decompression are concentrated to dryness, residue silica gel column chromatography, dichloromethane：First Alcohol=100：1 is eluant, eluent, obtains yellow oil (0.26g, 40%).ESI-MSm/z 320.9[M+H]+.1H NMR (300MHz,DMSO-d6):δ 8.28 (1H, d, J=9.0Hz), 7.53 (1H, d, J=7.8Hz), 7.29-7.34 (3H, m), 7.14-7.17 (1H, m), 6.93 (1H, dd, J=9.0Hz, 2.1Hz), 6.42 (1H, d, J=2.1Hz), 6.24 (1H, d, J= 7.8Hz), 5.23 (2H, s), 3.78 (4H, t, J=4.8Hz), 3.12 (4H, t, J=4.8Hz)13C NMR(75MHz,CDCl3) δ177.8,153.8,143.6,141.9,135.6,129.4,128.4,128.2,126.3,120.4,113.0,110.2, 99.3,66.7,57.0,48.2.
Following synthetic route 3 depicts some intermediates for preparing the compounds of this invention and some compounds of the present invention Conventional method.
Synthetic route 3：
Compound 18a-d General Synthetic Procedures
Ethyl 7- is substituted into -4 (1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) and 3- (diethylamino) propylamine (5.0ml) is mixed, 150 DEG C of microwave heating responses 30 minutes.Reaction solution is cooled down to room temperature, 100ml is added into reaction mixture Water, dichloromethane extraction (50mL × 3), merge organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filter, decompression It is concentrated to dryness, silica gel column chromatography, dichloromethane：Methanol=50：1 is eluant, eluent, obtains target product.
Embodiment 13：Prepare (1H)-Oxoquinoline -3- formamide (chemical combination of N- (3- (diethylamino) propyl group) -7- fluoro- 4 Thing 18a)
With (the 1H)-Oxoquinoline-3-carboxylic acid ester 4a (5.0mmol) of ethyl 7- fluoro- 4 for raw material, obtain white solid (0.72, 45%) .ESI-MS m/z 320 [M+H]+.1H NMR(300MHz,CDCl3)δ10.45(s,1H),8.82(s,1H),8.35- 8.40 (m, 1H), 7.23-7.27 (m, 1H), 7.08-7.14 (m, 1H), 3.56 (q, J=5.1Hz, 2H), 2.53-2.60 (m, 6H), 1.78-1.88 (m, 2H), 1.02 (t, J=6.9Hz, 6H)13CNMR(75MHz,CDCl3)δ176.6,166.4,163.4, 144.6,141.8,129.1,123.8,114.2,111.3,104.8,50.5,47.0,38.0,27.4,11.6.
Embodiment 14：Prepare 7- chloro- N- (3- (diethylamino) propyl group) -4 (1H)-Oxoquinoline -3- formamide (chemical combination Thing 18b)
With (the 1H)-Oxoquinoline-3-carboxylic acid ester 4b (5.0mmol) of ethyl 7- chloro- 4 for raw material, obtain white solid (0.87g, 52%) .ESI-MS m/z 336 [M+H]+.1H NMR(300MHz,CDCl3)δ10.48(s,1H),8.84(s,1H),8.34(d, J=8.7Hz, 1H), 7.63 (d, J=1.5Hz, 1H), 7.36 (dd, J=8.7,1.5Hz, 1H), 3.55 (q, J=5.1Hz, 2H), 2.58-2.65 (m, 6H), 1.78-1.94 (m, 2H), 1.07 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ 176.7,166.4,144.6,140.9,138.8,127.9,125.8,125.4,118.9,111.5,50.5,47.1,38.1, 27.4,11.6.
Embodiment 15：Prepare 7- bromo- N- (3- (diethylamino) propyl group) -4 (1H)-Oxoquinoline -3- formamide (chemical combination Thing 18c)
With (the 1H)-Oxoquinoline-3-carboxylic acid ester 4c (5.0mmol) of ethyl 7- bromo- 4 for raw material, obtain white solid (0.93, 49%) .ESI-MS m/z 380 [M+H]+.1H NMR(300MHz,CDCl3)δ10.52(s,1H),8.84(s,1H),8.26(d, J=8.7Hz, 1H), 7.81 (d, J=1.5Hz, 1H), 7.51 (dd, J=8.7,1.5Hz, 1H), 3.56 (q, J=5.1Hz, 2H), 2.58-2.65 (m, 6H), 1.82-1.91 (m, 2H), 1.06 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ 176.8,166.5,144.5,141.1,128.6,127.9,127.2,125.8,122.1,111.5,50.6,47.1,38.1, 27.4,11.7.
Embodiment 16：Prepare N- (3- diethylaminos) propyl group -7- methoxyl groups -4- (1H)-Oxoquinoline -3- formamides (compound 18d)
With (the 1H)-Oxoquinoline-3-carboxylic acid ester 4d (5.0mmol) of ethyl 7- methoxyl groups -4 for raw material, white solid is obtained (0.96g, 58%) .ESI-MS m/z332 [M+H]+.1H NMR(300MHz,CDCl3)δ10.50(s,1H),8.78(s,1H), 8.30 (d, J=9.0Hz, 1H), 7.00 (dd, J=9.0,1.8Hz, 1H), 6.91 (d, J=1.8Hz, 1H), 3.89 (s, 3H), 3.54 (q, J=5.4Hz, 2H), 2.51-2.59 (m, 6H), 1.78-1.87 (m, 2H), 1.02 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ176.6,166.3,162.9,143.1,141.1,127.6,120.7,115.8,110.8,99.7, 55.6,50.3,46.7,37.8,27.2,11.4.
Following synthetic route 4 depicts some intermediates for preparing the compounds of this invention and some compounds of the present invention Conventional method.
Synthetic route 4：
Compound 19a-f General Synthetic Procedures
Added in 100ml round-bottomed flask (the 1H)-Oxoquinoline-3-carboxylic acid ester 4b of ethyl 7- chloro- 4 (2.51g, 10mmol) with DMF (50ml), it is stirred at room temperature 10 minutes, then adds 60%NaH (0.8g, 20mmol), be stirred at room temperature 15 points Clock, corresponding halogenated alkane (15-30mmol) is then added, reaction, TLC tracing detections is stirred at room temperature.Reaction finishes, and reaction is mixed Close liquid to be poured into water, ethyl acetate extraction, merge organic phase, washing, saturated salt washing.Organic phase is acidified with concentrated hydrochloric acid, added Pressure is concentrated to dryness, and absolute ethyl alcohol band water 3 times, acetone recrystallization, filters to obtain yellow solid.Above-mentioned yellow solid is dissolved in water, carbon Sour hydrogen soda, ethyl acetate extraction, washing, saturated salt washing, anhydrous sodium sulfate drying, it is concentrated under reduced pressure into dry, silica gel column layer Analysis, ethyl acetate/petroleum ether=2:1 elution, obtains target product.
Embodiment 17：Prepare the chloro- 1- methyl -4- oxo-quinolines -3- carboxylates (compound 19a) of ethyl 7-
With iodomethane (15mmol) for raw material, white solid (1.7g, 65%) .ESI-MS m/z 288 [M+Na] are obtained+.1H NMR(300MHz,CDCl3) δ 8.42-8.45 (m, 2H), 7.38-7.41 (m, 2H), 4.39 (q, J=7.2Hz, 2H), 3.86 (s, 3H), 1.42 (t, J=7.2Hz, 3H)13CNMR(75MHz,CDCl3)δ172.9,164.9,151.2,141.3,138.2, 128.8,127.1,125.8,117.7,110.8,60.6,41.8,15.1.
Embodiment 18：Prepare the chloro- 1- ethyls -4- oxo-quinolines -3- carboxylates (compound 19b) of ethyl 7-
With iodoethane (15mmol) for raw material, white solid (1.9g, 69%) .ESI-MS m/z 302 [M+Na] are obtained+.1H NMR(300MHz,CDCl3) δ 8.44-8.47 (m, 2H), 7.25-7.43 (m, 2H), 4.39 (q, J=7.2Hz, 2H), 4.21 (q, J=7.2Hz, 2H), 1.56 (t, J=7.2Hz, 3H), 1.41 (t, J=7.2Hz, 3H)13C NMR(75MHz,CDCl3)δ 173.5,165.2,148.9,139.4,139.1,129.5,127.5,125.5,115.8,111.5,61.1,49.2,14.7.
Embodiment 19：Prepare the chloro- 4- oxo-quinolines -3- carboxylates (compound 19c) of ethyl 1- pi-allyls -7-
With allyl bromide, bromoallylene (15mmol) for raw material, white solid (2.2g, 75%) .ESI-MS m/z 314 [M+Na] are obtained+ .1H NMR(300MHz,CDCl3) δ 8.48 (s, 1H), 8.42 (d, J=8.7Hz, 1H), 7.34-7.39 (m, 2H), 5.94-5.07 (m, 1H), 5.40 (d, J=10.5Hz, 1H), 5.20 (d, J=17.1Hz, 1H), 4.79 (m, 2H), 4.38 (q, J=6.9Hz, 2H), 1.41 (t, J=6.9Hz, 3H)13C NMR(75MHz,CDCl3)δ173.8,165.2,149.7,140.0,139.2, 130.5,129.4,127.3,125.8,119.8,116.5,111.6,61.2,56.2,14.8.
Embodiment 20：Prepare the chloro- 4- oxo-quinolines -3- carboxylates (compound 19d) of ethyl 1- butyl -7-
With iodo-n-butane (30mmol) for raw material, [the M+Na of white solid (1.9g, 62%) .ESI-MS m/z 330 are obtained ]+.1H NMR(300MHz,DMSO-d6):δ 8.62 (s, 1H), 8.17 (d, J=8.7Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 7.47 (dd, J=8.7Hz, 1.8Hz, 1H), 4.33 (t, J=7.2Hz, 2H), 4.20 (q, J=7.2Hz, 2H), 1.64-1.73 (m, 2H), 1.24-1.34 (m, 5H), 0.88 (t, J=7.2Hz, 3H)13CNMR(75MHz,CDCl3)δ172.8,165.0, 150.5,140.3,138.4,129.2,127.5,125.8,117.4,111.1,60.7,53.3,31.3,19.9,15.1, 14.3.
Embodiment 21：Prepare the chloro- 4- oxo-quinolines -3- carboxylates (compound 19e) of ethyl 1- benzyls -7-
With cylite (15mmol) for raw material, white solid (2.9g, 85%) .ESI-MS m/z 364 [M+Na] are obtained+.1H NMR(300MHz,DMSO-d6):δ 8.54 (s, 1H), 8.43 (d, J=8.1Hz, 1H), 7.30-7.38 (m, 5H), 7.14-7.18 (m, 2H), 5.34 (s, 2H), 4.38 (q, J=7.2Hz, 2H), 1.41 (t, J=7.2Hz, 3H)13C NMR(75MHz,CDCl3) δ173.6,165.0,150.0,140.1,139.1,134.0,129.5,129.4,128.8,127.5,126.4,125.7, 116.7,111.7,61.1,57.5,14.8.
Embodiment 22：Prepare the chloro- 1- of ethyl 7- (3- phenylpropyls) -4- oxo-quinoline -3- carboxylates (compound 19f)
With 1- (3- bromopropyls) benzene (50mmol) for raw material, [the M of white solid (2.4g, 65%) .ESI-MS m/z 392 are obtained +Na]+.1H NMR(300MHz,CDCl3) δ 8.44 (d, J=8.7Hz, 1H), 8.37 (s, 1H), 7.43-7.15 (m, 7H), 4.40 (q, J=7.2Hz, 2H), 4.10 (t, J=7.2Hz, 2H), 2.77 (t, J=7.2Hz, 2H), 2.32-2.20 (m, 2H), 1.42 (t, J=7.2Hz, 3H)13C NMR(75MHz,CDCl3)δ173.2,164.9,149.1,139.2,139.1,138.8, 129.4,128.6,128.1,127.9,127.3,126.5,125.3,115.3,111.2,60.8,52.9,32.3,29.6, 14.4.
Following General Synthetic Procedures depict the conventional method for preparing the compounds of this invention compound 20a-k and 21a-e.
By 1- (the 1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) of ethyl 7- chloro- 4 substituted and corresponding diamines (5.0ml) is mixed, 150 DEG C of microwave heating responses 30 minutes.Reaction solution is cooled down to room temperature, 100ml is added into reaction mixture Water, dichloromethane extraction (50mL × 3), merge organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filter, decompression It is concentrated to dryness, silica gel column chromatography, dichloromethane：Methanol=50：1 is eluant, eluent, obtains target product.
Embodiment 23：Prepare 7- chloro- N- [2- (diethylamino) ethyl] -1- methyl -4- oxo-quinoline -3- formamides (compound 20a)
With the chloro- 1- methyl -4- oxo-quinolines -3- carboxylates 19a (5.0mmol) of ethyl 7- and N, N- diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.1g, 68%) .ESI-MS m/z 336 [M+H]+.1H NMR(300MHz,CDCl3)δ 9.92 (s, 1H), 8.73 (s, 1H), 8.45 (d, J=8.4Hz, 1H), 7.43-7.50 (m, 2H), 3.91 (s, 3H), 3.55 (q, J =6.3Hz, 2H), 2.61-2.67 (m, 6H), 1.79-1.91 (m, 2H), 1.08 (t, J=7.2Hz, 6H)13C NMR(75MHz, CDCl3)δ176.0,164.6,148.8,140.7,139.5,129.1,126.3,125.9,116.0,112.7,52.1,47.5, 41.8,37.7,12.2.
Embodiment 24：Prepare 7- chloro- N- [3- (diethylamino) propyl group] -1- methyl -4- oxo-quinoline -3- formamides (compound 20b)
With the chloro- 1- methyl -4- oxo-quinolines -3- carboxylates 19a (5.0mmol) of ethyl 7- and 3- (diethylamino) third Amine (5.0ml) is raw material, obtains white solid (0.9g, 54%) .ESI-MS m/z 350 [M+H]+.1H NMR(300MHz, CDCl3) δ 9.92 (s, 1H), 8.73 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.43-7.50 (m, 2H), 3.91 (s, 3H), 3.55 (q, J=6.3Hz, 2H), 2.61-2.67 (m, 6H), 1.79-1.91 (m, 2H), 1.08 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ176.1,164.6,148.9,140.7,139.6,129.0,125.9,116.0,112.7,50.6, 47.1,41.8,38.0,27.4,11.9.
Embodiment 25：Prepare 7- chloro- N- [2- (diethylamino) ethyl] -1- ethyl -4- oxo-quinoline -3- formamides (compound 20c)
With the chloro- 1- ethyls -4- oxo-quinolines -3- carboxylates 19b (5.0mmol) of ethyl 7- and N, N- diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.0g, 58%) .ESI-MS m/z 350 [M+H]+.1H NMR(300MHz,CDCl3)δ 9.95 (s, 1H), 8.77 (s, 1H), 8.44 (d, J=8.4Hz, 1H), 7.50 (d, J=1.5Hz, 1H), 7.43 (d, J= 8.4Hz, 1.5Hz, 1H), 4.29 (q, J=7.2Hz, 2H), 3.55 (q, J=6.6Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 2.64 (q, J=7.2Hz, 4H), 1.57 (t, J=7.2Hz, 3H), 1.10 (t, J=7.2Hz, 6H)13C NMR(75MHz, CDCl3)δ175.9,164.7,147.6,139.6,139.4,129.3,126.6,125.6,115.7,112.9,52.1,49.3, 47.5,37.7,14.8,12.3.
Embodiment 26：Prepare 7- chloro- N- [2- (diethylamino) propyl group] -1- ethyl -4- oxo-quinoline -3- formamides (compound 20d)
With the chloro- 1- ethyls -4- oxo-quinolines -3- carboxylates 19b (5.0mmol) of ethyl 7- and 3- (diethylamino) third Amine (5.0ml) is raw material, obtains white solid (1.06g, 57%) .ESI-MS m/z 364 [M+H]+.1H NMR(300MHz, CDCl3) δ 9.92 (s, 1H), 8.77 (s, 1HH), 8.45 (d, J=8.7Hz, 1H), 7.51 (d, J=1.8Hz, 1H), 7.43 (dd, J=8.7,1.8Hz, 1H), 4.28 (q, J=7.2Hz, 2H), 3.49 (q, J=6.9Hz, 2H), 2.54 (m, 6H), 1.86- 1.74 (m, 2H), 1.57 (t, J=7.2Hz, 3H), 1.04 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ176.0, 164.6,147.7,139.5,129.3,126.6,125.7,115.7,112.9,50.7,49.4,47.2,38.0,27.6, 14.9,12.1.
Embodiment 27：Prepare 1- pi-allyls -7- chloro- N- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formyls Amine (compound 20e)
With the chloro- 4- oxo-quinolines -3- carboxylates 19c (5.0mmol) of ethyl 1- pi-allyls -7- and N, N- diethyl second two Amine (5.0ml) is raw material, obtains white solid (0.96g, 53%) .ESI-MS m/z 362 [M+H]+.1H NMR(300MHz, CDCl3) δ 10.00 (s, 1H), 8.75 (s, 1H), 8.44 (d, J=8.7Hz, 1H), 7.46 (d, J=1.5Hz, 1H), 7.42 (dd, J=8.7,1.5Hz, 1H), 5.94-6.07 (m, 1H), 5.40 (d, J=10.2Hz, 1H), 5.20 (d, J=17.1Hz, 1H), 4.81-4.84 (m, 2H), 3.64 (q, J=6.6Hz, 2H), 2.82 (t, J=6.6Hz, 2H), 2.74 (q, J=6.9Hz, 4H), 1.17 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ176.0,164.6,148.3,140.1,139.4, 130.3,129.1,126.4,125.8,119.9,116.4,112.9,56.2,52.1,47.5,37.8.12.2.
Embodiment 28：Prepare 1- pi-allyls -7- chloro- N- [3- (diethylamino) propyl group] -4- Oxoquinoline -3- formamides (compound 20f)
With the chloro- 4- oxo-quinolines -3- carboxylates 19c (5.0mmol) of ethyl 1- pi-allyls -7- and 3- (diethylamino) Propylamine (5.0ml) is raw material, obtains white solid (1.24g, 66%) .ESI-MS m/z 376 [M+H]+.1H NMR(300MHz, CDCl3) δ 9.91 (s, 1H), 8.76 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.40- 7.44 (m, 1H), 5.94-6.07 (m, 1H), 5.40 (d, J=10.5Hz, 1H), 5.20 (d, J=17.1Hz, 1H), 4.81- 4.83 (m, 2H), 3.50 (q, J=6.6Hz, 2H), 2.56-2.63 (m, 6H), 1.79-1.89 (m, 2H), 1.08 (t, J= 7.2Hz,6H).13C NMR(75MHz,CDCl3)δ171.4,159.8,143.4,135.4,134.7,125.5,124.4, 121.7,121.1,115.3,111.7,108.3,51.5,46.0,42,5,33.3,22.8,7.4.
Embodiment 29：Prepare 1- butyl -7- chloro- N- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formamides (compound 20g)
With the chloro- 4- oxo-quinolines -3- carboxylates 19d (5.0mmol) of ethyl 1- butyl -7- and N, N- diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.23g, 65%) .ESI-MS m/z 378 [M+H]+.1H NMR(300MHz,CDCl3) δ 9.96 (s, 1H), 8.72 (s, 1H), 8.46 (d, J=8.7Hz, 1H), 7.49 (d, J=1.5Hz, 1H), 7.43 (dd, J= 8.7,1.5Hz, 1H), 4.20 (t, J=7.2Hz, 2H), 3.58 (q, J=6.6Hz, 2H), 2.73 (t, J=6.6Hz, 2H), 2.66 (q, J=6.9Hz, 4H), 1.84-1.94 (m, 2H), 1.40-1.52 (m, 2H), 1.10 (t, J=7.2Hz, 6H), 1.01 (t, J=7.2Hz, 3H)13C NMR(75MHz,CDCl3)δ175.9,164.7,148.2,139.9,139.4,129.4, 126.7,125.7,115.8,112.7,54.3,52.2,47.6,37.8,31.2,20.3,13.9,12.3.
Embodiment 30：Prepare 1- butyl -7- chloro- N- [3- (diethylamino) propyl group] -4- oxo-quinoline -3- formamides (compound 20h)
With the chloro- 4- oxo-quinolines -3- carboxylates 19d (5.0mmol) of ethyl 1- butyl -7- and 3- (diethylamino) third Amine (5.0ml) is raw material, obtains white solid (1.22g, 63%) .ESI-MS m/z 392 [M+H]+.1H NMR(300MHz, CDCl3) δ 9.96 (s, 1H), 8.72 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.49 (d, J=1.5Hz, 1H), 7.43 (dd, J=8.7,1.5Hz, 1H), 4.21 (t, J=7.5Hz, 2H), 3.50 (q, J=6.6Hz, 2H), 2.65-2.71 (m, 6H), 1.84-1.94 (m, 4H), 1.40-1.52 (m, 2H), 1.13 (t, J=7.2Hz, 6H), 1.02 (t, J=7.2Hz, 3H)13CNMR (75MHz,CDCl3)δ176.0,164.6,148.2,139.9.139.4,129.3,126.6,125.7,115.9,112.7, 54.3,50.8,47.2,38.1,31.2,27.6,20.3,14.0,12.1.
Embodiment 31：Prepare 1- benzyls -7- chloro- N- [2- (diethylamino) ethyl] -4- oxo-quinoline -3- formamides (compound 20i)
The chloro- 4- oxo-quinolines -3- carboxylates 19e (5mmol) of ethyl 1- benzyls -7- and N, N- diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.4g, 68%) .ESI-MS m/z 412 [M+H]+.1H NMR(300MHz,CDCl3)δ 9.94 (s, 1H), 8.88 (s, 1H), 8.45 (d, J=9.0Hz, 1H), 7.32-7.39 (m, 5H), 7.15-7.17 (m, 2H), 5.40 (s, 2H), 3.57 (q, J=6.6Hz, 2H), 2.72 (t, J=6.6Hz, 2H), 2.63 (q, J=7.2Hz, 4H), 1.09 (t, J=7.2Hz, 6H)13C NMR(75MHz,CDCl3)δ176.1,164.6,148.9,140.2,139.4,134.0, 129.6,129.2,128.9,126.7,126.4,125.6,116.7,113.0,57.852.1,47.6,37.8,12.3.
Embodiment 32：Prepare 1- benzyls -7- chloro- N- [2- (diethylamino) propyl group] -4- oxo-quinoline -3- formamides (compound 20j)
The chloro- 4- oxo-quinolines -3- carboxylates 19e (5mmol) of ethyl 1- benzyls -7- and 3- (diethylamino) propylamine (5.0ml) is raw material, obtains white solid (1.2g, 56%) .ESI-MS m/z 426 [M+H]+.1H NMR(300MHz,DMSO- d6):δ 10.04 (s, 1H), 8.85 (1H, s), 8.41 (d, J=9.0Hz, 1H), 7.34-7.40 (m, 5H), 7.14-7.16 (m, 2H), 5.42 (s, 2H), 3.55 (q, J=6.3Hz, 2H), 2.90-3.01 (m, 6H), 1.82-1.87 (m, 2H), 1.29 (t, J= 7.2Hz,6H).13C NMR(75MHz,CDCl3)δ176.2,164.5,149.0,140.2,139.5,133.9,129.6, 129.2,129.0,126.6,126.4,125.9,116.7,113.0,57.9,50.7,47.2,38.1,27.5,12.0.
Embodiment 33：Prepare 7- chloro- N- [3- (diethylamino) propyl group] -1- (3- phenylpropyls) -4- oxo-quinolines -3- Formamide (compound 20k)
With the chloro- 1- of ethyl 7- (3- phenylpropyls) -4- oxo-quinoline -3- carboxylates 19f (5.0mmol) and 3- (diethyl aminos Base) propylamine (5.0ml) is raw material, obtain white solid (1.4g, 63%) .ESI-MS m/z 454 [M+H]+.1H NMR(300MHz, CDCl3) δ 9.91 (s, 1H), 8.71 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.40 (d, J=8.7Hz, 1H), 7.37- 7.17 (m, 6H), 4.17 (t, J=7.2Hz, 2H), 3.48 (q, J=6.6Hz, 2H), 2.78 (t, J=7.2Hz, 2H), 2.53- 2.60 (m, 6H), 2.19-2.30 (m, 2H), 1.76-1.86 (m, 2H), 1.05 (t, J=7.2Hz, 6H)13C NMR(75MHz, CDCl3)δ175.6,164.2,147.8,139.4,139.1,128.9,128.7,128.1,126.5,126.2,125.4, 115.4,112.3,53.1,50.3,46.8,37.6,32.4,30.0,27.0,11.6.
Embodiment 34：Prepare the chloro- 1- ethyls -4- oxo-quinolines -3- formamide (compounds of N- (3- aminopropyls) -7- 21a)
With the chloro- 1- ethyls -4- oxo-quinolines -3- carboxylates 19b (5.0mmol) of ethyl 7- and 1,3- propane diamine (5.0ml) For raw material, white solid (0.9g, 60%) .ESI-MS m/z 308 [M+H] are obtained+.1H NMR(300MHz,CDCl3)δ9.95(s, 1H), 8.77 (s, 1H), 8.44 (d, J=8.7Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.7Hz, 1H), 4.29 (q, J= 7.2Hz, 2H), 3.55 (q, J=6.3Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 1.72-1.92 (m, 2H), 1.57 (t, J= 7.2Hz,3H).13C NMR(75MHz,CDCl3)δ176.0,164.9,147.7,139.6,129.2,126.5,125.8, 115.8,112.7,49.4,39.7,36.7,33.7,14.9.
Embodiment 35：Prepare the chloro- 4- oxo-quinolines -3- formamide (compounds of 1- pi-allyls-N- (3- aminopropyls) -7- 21b)
With the chloro- 4- oxo-quinolines -3- carboxylates 19c (5.0mmol) of ethyl 1- pi-allyls -7- and 1,3- propane diamine (5.0ml) is raw material, obtains white solid (0.9g, 58%) .ESI-MS m/z 320 [M+H]+.1H NMR(300MHz,CDCl3)δ 9.91 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.41-7.48 (m, 2H), 5.94-6.07 (m, 1H), 5.39 (d, J=10.5Hz, 1H), 5.19 (d, J=17.1Hz, 1H), 4.82-4.84 (m, 2H), 3.55 (q, J=6.6Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 1.69-1.81 (m, 2H)13C NMR(75MHz,CDCl3)δ176.1,165.0, 164.8,148.5,140.3,140.1,139.5,130.3,129.0,126.4,125.9,120.0,116.5,112.7,56.3, 39.6,36.8,33.5.
Embodiment 36：Prepare the chloro- 4- oxo-quinolines -3- formamide (compounds of N- (3- aminopropyls) -1- butyl -7- 21c)
With the chloro- 4- oxo-quinolines -3- carboxylates 19d (5.0mmol) of ethyl 1- butyl -7- and 1,3- propane diamine (5.0ml) For raw material, white solid (1.2g, 70%) .ESI-MS m/z 336 [M+H] are obtained+.1H NMR(300MHz,CDCl3)δ9.98(s, 1H), 8.74 (s, 1H), 8.46 (d, J=8.7Hz, 1H), 7.51 (d, J=1.8Hz, 1H), 7.44 (dd, J=8.7,1.8Hz, 1H), 4.23 (t, J=7.5Hz, 2H), 3.52 (q, J=6.6Hz, 2H), 2.78 (t, J=6.3Hz, 2H), 1.80-1.91 (m, 4H), 1.40-1.52 (m, 2H), 1.03 (t, J=7.2Hz, 3H)13C NMR(75MHz,CDCl3)δ176.1,165.7, 148.5,139.7.139.3,128.9,126.2,125.6,115.8,111.6,54.1,38.0,36.1,30.9,27.9, 19.9,13.6.
Embodiment 37：Prepare the chloro- 1- benzyls -4- oxo-quinolines -3- formamide (compounds of N- (3- aminopropyls) -7- 21d)
With the chloro- 1- benzyls -4- oxo-quinolines -3- carboxylates 19e (5.0mmol) of ethyl 7- and 1,3- propane diamine (5.0ml) For raw material, white solid (1.1g, 62%) .ESI-MS m/z 370 [M+H] are obtained+.1H NMR(300MHz,DMSO-d6):δ9.95 (s, 1H), 8.89 (s, 1H), 8.43 (d, 1H, J=9.3Hz), 7.34-7.40 (m, 5H), 7.14-7.16 (m, 2H), 5.42 (s, 2H), 3.56 (q, J=6.6Hz, 2H), 2.84 (t, J=6.6Hz 2H), 1.84-1.88 (m, 2H)13C NMR(75MHz, CDCl3)δ176.2,164.7,148.9,140.1,139.4,133.7,129.5,129.0,128.9,126.5,126.2, 125.8,116.5,112.7,57.6,39.5,36.5,33.4.
Embodiment 38：N- (3- aminopropyls) -7- chloro- 1- (3- phenylpropyls) -4- oxo-quinoline -3- formamides are prepared (to change Compound 21e)
With the chloro- 1- of ethyl 7- (3- phenylpropyls) -4- oxo-quinoline -3- carboxylates 19f (5.0mmol) and 1,3- propane diamine (5.0ml) is raw material, obtains white solid (0.9g, 45%) .ESI-MS m/z 398 [M+H]+.1H NMR(300MHz,CDCl3)δ 9.97 (s, 1H), 8.71 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.14 (m, 6H), 4.18 (t, J=7.2Hz, 2H), 3.57 (q, J=6.9Hz, 2H), 2.85 (t, J=6.6Hz, 2H), 2.79 (t, J=7.2Hz, 2H),2.34–2.20(m,2H),1.76–1.88(m,2H).13C NMR(75MHz,CDCl3)δ175.6,164.5,147.8, 139.4,139.1,128.8,128.7,128.1,126.5,126.2,125.5,115.4,112.2,53.2,39.3,36.4, 33.3,32.4,30.0.
Following synthetic route 5 depicts prepare compound 8a and compound 8b and compound 9a to 9e conjunction in general manner Into process.
Synthetic route 5：
Compound 8a-b General Synthetic Procedures：By the chloro- 4- of 7- (1H)-Oxoquinoline 6b or 7- methoxyl group -4- (1H)-oxygen Added for quinoline 6d (10mmol) in round-bottomed flask, then add POCl3(20ml), mixed liquor is heated to reflux 1h.Cooling reaction Liquid, add POCl3(10ml), continue back flow reaction 1h.Reaction finishes, cooling reaction solution to room temperature.Reaction solution is poured slowly into In frozen water (very exothermic), sodium hydroxide solution regulation pH to 9.0, white fluffy solid is separated out, is filtered, washing, dries and (easily rises China), obtain pale solid.
Embodiment 39：Prepare 4,7- dichloroquinolines (compound 8a)
With (the 1H)-Oxoquinoline 6b (10mmol) of 7- chloro- 4 for raw material, white solid (1.68g, 85%) is obtained.ESI-MS m/z 197[M]+.1HNMR(300MHz,CDCl3):δ 8.74 (1H, d, J=4.8Hz), 8.09-8.15 (2H, m), 7.54-7.58 (1H, m), 7.45 (1H, d, J=4.8Hz)13CNMR(75MHz,CDCl3)δ151.0,149.4,142.8,136.7,128.8 (2C),125.7,125.1,121.6.
Embodiment 40：Prepare the chloro- 7- methoxy quinolines (compound 8b) of 4-
With 7- methoxyl groups -4 (1H)-Oxoquinoline 6d (10mmol) for raw material, white solid (1.7g, 88%) is obtained.ESI- MS m/z 194[M+H]+.1HNMR(300MHz,CDCl3):δ 8.67 (1H, d, J=4.8Hz), 8.09 (1H, d, J=9.0Hz), 7.42 (1H, d, J=2.4Hz), 7.33 (1H, d, J=4.8Hz), 7.28 (1H, dd, J=9.0Hz, J=2.4Hz), 3.97 (3H,s).13C NMR(75MHz,CDCl3)δ161.3,151.0,150.2,142.4,125.3,121.7,120.8,119.3, 107.7,55.9.
Embodiment 41：Prepare 7- chloro-4-methoxy quinoline (compound 9a)
Absolute methanol (50ml) is added in 100ml round-bottomed flasks, metallic sodium (1.05g, 50mmol) is then added, treats gold After belonging to sodium disappearance, 4,7- dichloro-quinolines (10mmol) are added, are heated to reflux 2h.Reaction finishes, and cooling reaction solution subtracts to room temperature Pressure steam remaining methanol, obtain white solid, into bottle add 50ml water, filter, wash, dry, obtain pale solid (1.66g, 84%).ESI-MS m/z 194[M+H]+.1HNMR(300MHz,CDCl3):δ 8.71 (1H, d, J=5.1Hz), 8.09 (1H, d, J=8.7Hz), 7.99 (1H, d, J=2.1Hz), 7.40 (1H, dd, J=8.7Hz, J=2.1Hz), 6.70 (1H, d, J= 5.1Hz),4.03(3H,s).13C NMR(75MHz,CDCl3)δ162.4,152.7,149.7,135.8,128.0,126.7, 123.6,120.0,100.6,56.1.
Embodiment 42：Prepare the chloro- 4- ethoxyquinolines (compound 9b) of 7-
Absolute ethyl alcohol (50ml) is added in 100ml round-bottomed flasks, metallic sodium (1.05g, 50mmol) is then added, treats gold After belonging to sodium disappearance, 4,7- dichloro-quinolines (10mmol) are added, are heated to reflux 2h.Reaction finishes, and cooling reaction solution subtracts to room temperature Pressure steam remaining ethanol, obtain white solid, into bottle add 50ml water, filter, wash, dry, obtain pale solid (1.8g, 87%).ESI-MS m/z 208[M+H]+.1HNMR(300MHz,CDCl3):δ 8.68 (1H, d, J=5.1Hz), 8.11 (1H, d, J=9.0Hz), 7.98 (1H, d, J=2.1Hz), 7.39 (1H, dd, J=8.7Hz, J=2.1Hz), 6.67 (1H, d, J= 5.1Hz), 4.21 (2H, q, J=6.9Hz), 1.54 (3H, t, J=7.2Hz)13C NMR(75MHz,CDCl3)δ161.7, 152.6,149.8,135.7,128.0,126.5,123.7,120.0,101.1,64.6,14.8.
Embodiment 43：Prepare the chloro- 4- isopropoxies quinoline (compound 9c) of 7-
Isopropanol (50ml) is added in 100ml round-bottomed flasks, metallic sodium (1.05g, 50mmol) is then added, treats metal After sodium disappears, 4,7- dichloro-quinolines (10mmol) are added, are heated to reflux 8h.TLC tracing detections, reaction finish, and cool down reaction solution To room temperature, decompression steams remaining isopropanol, obtains yellow oil, and water (50ml), dichloromethane extraction three are added into residue It is secondary, washing, saturated salt washing, anhydrous sodium sulfate drying, it is concentrated under reduced pressure into dry, silica gel column chromatography, methylene chloride/methanol=200: 1 elution, is concentrated under reduced pressure into dry, obtains yellow oil (1.51g, 68%).ESI-MS m/z 222[M+H]+.1H NMR (300MHz,CDCl3):δ 8.68 (1H, d, J=5.1Hz), 8.12 (1H, d, J=8.7Hz), 7.98 (1H, d, J=2.1Hz), 7.41 (1H, dd, J=8.7Hz, J=2.1Hz), 6.69 (1H, d, J=5.1Hz), 4.78-4.86 (1H, m), 1.50 (3H, s), 1.48(3H,s).13C NMR(75MHz,CDCl3)δ160.8,152.5,150.1,135.7,127.9,126.4,123.9, 120.7,101.8,71.3,22.1.
Embodiment 44：Prepare 4,7- dimethoxy-quinolines (compound 9d)
Methanol (50ml) is added in 100ml round-bottomed flasks, metallic sodium (1.05g, 50mmol) is then added, treats metallic sodium After disappearance, the chloro- 7- methoxy quinolines (10mmol) of 4- are added, are heated to reflux 8h.TLC tracing detections, reaction finish, cooling reaction Liquid to room temperature, decompression steams remaining methanol, obtains yellow oil, and water (50ml), dichloromethane extraction three are added into residue It is secondary, washing, saturated salt washing, anhydrous sodium sulfate drying, it is concentrated under reduced pressure into dry, silica gel column chromatography, petroleum ether/acetone=4:1 washes It is de-, it is concentrated under reduced pressure into dry, obtains white solid (1.66g, 88%).ESI-MSm/z 190[M+H]+.1H NMR(300MHz, CDCl3):δ 8.63 (1H, d, J=5.1Hz), 8.04 (1H, d, J=9.0Hz), 7.34 (1H, d, J=2.4Hz), 7.12 (1H, Dd, J=9.0Hz, J=2.4Hz), 6.60 (1H, d, J=5.1Hz), 4.00 (3H, s), 3.93 (3H, s)13C NMR(75MHz, CDCl3)δ162.3,160.9,151.8,151.1,123.1,118.3,116.1,107.3,98.9,55.7,55.6.
Embodiment 45：Prepare 4- ethyoxyl -7- methoxy quinolines (compound 9e)
Absolute ethyl alcohol (50ml) is added in 100ml round-bottomed flasks, metallic sodium (1.05g, 50mmol) is then added, treats gold After belonging to sodium disappearance, the chloro- 7- methoxy quinolines (10mmol) of 4- are added, it is heated to reflux 2h.Reaction finishes, cooling reaction solution to room Temperature, decompression steam remaining ethanol, and 50ml water is added into residue, ethyl acetate extraction (100ml × 3), merges organic phase, water Wash, saturated salt washing, anhydrous sodium sulfate drying, filtering, be concentrated under reduced pressure into dry, obtain pale yellow oil, silica gel column chromatography, oil Ether/acetone=4:1 elution, is concentrated under reduced pressure into dry, obtains white solid (1.58g, 78%).ESI-MS m/z 204[M+H]+.1H NMR(300MHz,CDCl3):δ 8.60 (1H, d, J=5.4Hz), 8.06 (1H, d, J=9.3Hz), 7.33 (1H, d, J= 2.4Hz), 7.11 (1H, dd, J=9.3Hz, J=2.4Hz), 6.56 (1H, d, J=5.4Hz), 4.20 (2H, q, J=6.9Hz), 3.92 (3H, s), 1.54 (3H, t, J=6.9Hz)13C NMR(75MHz,CDCl3)δ161.6,160.9,151.8,151.2, 123.3,118.1,116.1,107.2,99.4,64.1,55.6,14.7.
Following synthetic route 6 depicts prepare compound 12a and compound 12b and compound 13,14 in general manner Building-up process.
Synthetic route 6：
Embodiment 46：Prepare the chloro- 4- (1H) of 5,8- bis--Oxoquinoline (compound 13)
The sub- isopropyl ester (4.32g, 30mmol) of malonic acid and trimethyl orthoformate (53g, 500mmol) are mixed, heating Flow back 2h, then cools down reaction solution to room temperature, adds 2,5- dichloroanilines (3.24g, 20mmol), reaction mixture is heated to reflux 2h.Reaction solution is cooled down to room temperature, white crystal is separated out, filtering, methanol washing, obtains white solid.
Above-mentioned white solid is mixed with diphenyl ether (40ml), is heated to reflux 1h.Reaction solution is cooled down to room temperature, adds 50ml Petroleum ether, filtered after stirring, obtain brown solid 3.0g.Silica gel column chromatography, methylene chloride/methanol=25：1 elution, must change Compound 13 is white solid (2.5g, 69%).ESI-MS m/z 215[M+H]+.1H NMR(300MHz,CDCl3):δ11.23 (1H, s), 7.71-7.75 (2H, m), 7.26 (1H, d, J=7.2Hz), 6.08 (1H, d, J=7.2Hz)
Embodiment 47：Prepare the chloro- 4- (1H) of 6,8- bis--Oxoquinoline (compound 14)
The sub- isopropyl ester (4.32g, 30mmol) of malonic acid and trimethyl orthoformate (53g, 500mmol) are mixed, heating Flow back 2h, then cools down reaction solution to room temperature, adds 3,4-DCA (3.24g, 20mmol), reaction mixture is heated to reflux 2h.Reaction solution is cooled down to room temperature, white crystal is separated out, filtering, methanol washing, obtains white solid.
Above-mentioned white solid is mixed with diphenyl ether (40ml), is heated to reflux 1h.Reaction solution is cooled down to room temperature, adds 50ml Petroleum ether, filtered after stirring, obtain brown solid 3.0g.Recrystallizing methanol, obtain compound 14 for white solid (2.6g, 72%).ESI-MS m/z 215[M+H]+.1H NMR(300MHz,CDCl3):δ11.54(1H,s),7.96-7.99(2H,m), 7.85 (1H, d, J=6.9Hz), 6.13 (1H, d, J=6.9Hz)
Synthetic route 7：
Embodiment 48：Prepare the chloro- 7- oxyquinolines (compound 22) of 4-
By the chloro- 7- methoxy quinolines 8b (3.86g, 20mmol) of 4-, 40%HBr (30mL) and acetic anhydride (20mL) mixing after It is heated to reflux, TLC tracing detections, reaction finishes, cooling reaction solution to room temperature.Diluted then to 100mL water is added in reaction solution, 20%NaOH solution adjusts pH to 6.0, has a large amount of solids to separate out, and filters, and washes, and dries, obtain pale solid (3.53g, 98.6%).
Embodiment 49：Prepare the chloro- 7- ethoxyquinolines (compound 23a) of 4-
The chloro- 7- oxyquinolines (0.72g, 4mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.4g, 10mmol), 15min is stirred at room temperature, adds 1- bromoethanes (20mmol) and continue to react, TLC tracing detections.Reaction Finish, reaction mixture is poured into water, ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous slufuric acid Sodium is dried, and is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain light yellow solid (0.56g, yield 67.2%).Mp 70-71℃.MS(ESI):m/z(M+H)+207.8.1H NMR(300MHz,CDCl3)δ8.66 (d, J=4.7Hz, 1H, ArH), 8.09 (d, J=9.2Hz, 1H, ArH), 7.39 (d, J=1.8Hz, 1H, ArH), 7.32 (d, J =4.7Hz, 1H, ArH), 7.29-7.20 (m, 1H, ArH), 4.19 (q, J=6.9Hz, 2H, CH2), 1.50 (t, J=7.0Hz, 3H,CH3).13C NMR(75MHz,CDCl3)δ160.3,150.6,149.8,142.0,124.9,121.2,120.7,118.8, 107.8,63.7,14.6.
Embodiment 50：Prepare the chloro- 7- n-butoxies quinoline (compound 23b) of 4-
The chloro- 7- oxyquinolines (0.89g, 5mmol) of 4-, acetone (40ml) and anhydrous are added in 100ml round-bottomed flask K2CO3Backflow 15 minutes is stirred at room temperature in (2.0g), then adds iodo sign butane (20mmol), TLC tracing detections.Reaction finishes, It is evaporated under reduced pressure and removes acetone, adds 150mL water, ethyl acetate extraction, merge organic phase, add concentrated hydrochloric acid acidifying, absolute ethyl alcohol Band water, yellow oil is obtained, acetone recrystallization, white crystal is separated out, is alkalized after filtering, obtain white solid (0.57g, production Rate 47.6%).Mp 37-38℃.MS(ESI):m/z(M+H)+236.1.1HNMR(300MHz,CDCl3) δ 8.65 (d, J= 4.8Hz, 1H, ArH), 8.08 (d, J=9.2Hz, 1H, ArH), 7.39 (d, J=1.9Hz, 1H, ArH), 7.31 (d, J= 4.8Hz, 1H, ArH), 7.29-7.23 (m, 1H, ArH), 4.12 (t, J=6.5Hz, 2H, CH2CH2CH2CH3),1.92–1.79 (m,2H,CH2CH2CH2CH3),1.62–1.47(m,2H,CH2CH2CH2CH3), 1.00 (t, J=7.3Hz, 3H, CH2CH2CH2CH3).13C NMR(75MHz,CDCl3)δ160.5,150.7,149.8,142.0,124.9,121.2,120.8, 118.8,108.0,68.0,31.0,19.2,13.8.
Embodiment 50：Prepare the chloro- 7- positive hexyloxies quinoline (compound 23c) of 4-
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds isobutane bromide (3.5mmol) and continue to react, TLC tracing detections.Instead It should finish, reaction mixture is poured into water, ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sulphur Sour sodium is dried, and is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain yellow oil (0.22g, yield 68.0%).Mp yellow oil.MS(ESI):m/z(M+H)+263.9.1H NMR(300MHz,CDCl3)δ 8.65 (d, J=4.8Hz, 1H, ArH), 8.07 (d, J=9.2Hz, 1H, ArH), 7.38 (d, J=2.4Hz, 1H, ArH), 7.30 (d, J=4.8Hz, 1H, ArH), 7.26 (dd, J=9.1,2.5Hz, 1H, ArH), 4.11 (t, J=6.5Hz, 2H, OCH2(CH2)4CH3),1.94–1.79(m,1H,OCH2CH2(CH2)3CH3), 1.49 (dd, J=14.4,7.2Hz, 2H, O (CH2)2CH2(CH2)2CH3), 1.37 (dt, J=7.1,4.7Hz, 4H, O (CH2)3CH2CH2CH3), 0.91 (t, J=6.9Hz, 3H, CH3).13CNMR (75MHz,CDCl3)δ160.7,150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,68.4, 31.6,29.0,25.8,22.7,14.1.
Embodiment 50：Prepare the chloro- 7- allyloxys quinoline (compound 23d) of 4-
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds 1- bromine allyl alkane (3.5mmol) and continue to react, TLC tracing detections.Instead It should finish, reaction mixture is poured into water, ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sulphur Sour sodium is dried, and is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain light yellow solid (0.37g, yield 78.4%).Mp 36-37℃.MS(ESI):m/z(M+H)+219.8.1HNMR(300MHz,CDCl3)δ8.66 (d, J=4.6Hz, 1H, ArH), 8.09 (d, J=9.1Hz, 1H, ArH), 7.41 (s, 1H, ArH), 7.29 (dd, J=15.9, 6.2Hz, 2H, ArH), 6.10 (ddt, J=15.9,10.4,5.3Hz, 1H, CH2=CH), 5.48 (d, J=17.2Hz, 1H, CH2 =CH), 5.34 (d, J=10.4Hz, 1H, CH2=CH), 4.69 (d, J=4.8Hz, 2H, OCH2).13C NMR(75MHz, CDCl3)δ159.9,150.5,149.9,142.1,132.2,125.1,121.4,120.8,119.0,118.1,108.4, 68.9.
Embodiment 50：Prepare the chloro- 7- isopropoxies quinoline (compound 23e) of 4-
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds 1- bromines isopropyl alkane (3.5mmol) and continue to react, TLC tracing detections, instead Answer 24h.Reaction is finished, and reaction mixture is poured into water, and ethyl acetate extraction, merges organic phase, washing, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, be concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain pale yellow Color solid (0.28g, yield 54.6%).Mp 65-66℃.MS(ESI):m/z(M+H)+221.8.1H NMR(300MHz, CDCl3) δ 8.65 (d, J=4.7Hz, 1H, ArH), 8.08 (d, J=9.2Hz, 1H, ArH), 7.39 (s, 1H, ArH), 7.30 (d, J=4.7Hz, 1H, ArH), 7.27-7.20 (m, 1H, ArH), 4.82-4.67 (m, 1H, CH), 1.43 (d, J=6.0Hz, 6H, CH3).13C NMR(75MHz,CDCl3)δ159.3,150.5,149.7,142.1,125.0,121.5,121.0,118.7, 108.8,70.2,21.7.
Embodiment 50：Prepare the chloro- 7- isobutoxies quinoline (compound 23f) of 4-
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds isobutane bromide (3.5mmol) and continue to react, TLC tracing detections, instead Answer 8h.Reaction is finished, and reaction mixture is poured into water, and ethyl acetate extraction, merges organic phase, washing, and saturated common salt is washed, Anhydrous sodium sulfate drying, it is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain white solid Body (0.26g, yield 88.7%).Mp 57-58℃.MS(ESI):m/z(M+H)+235.8.1H NMR(300MHz,CDCl3)δ 8.65 (d, J=4.8Hz, 1H, ArH), 8.09 (d, J=9.2Hz, 1H, ArH), 7.38 (d, J=2.4Hz, 1H, ArH), 7.31 (d, J=4.8Hz, 1H, ArH), 7.28 (dd, J=9.2,2.4Hz, 1H, ArH), 3.88 (d, J=6.5Hz, 2H, CH2),2.18 (dp, J=13.3,6.6Hz, 1H, CH), 1.07 (d, J=6.7Hz, 6H, CH3).13C NMR(75MHz,CDCl3)δ160.7, 150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,74.7,28.1,19.3.
Embodiment 50：Prepare the chloro- 7- benyloxyquinolines (compound 23g) of 4-
The chloro- 7- oxyquinolines (0.89g, 5mmol) of 4-, acetone (40ml), cylite are added in 100ml round-bottomed flask (7.5mmol) and anhydrous K2CO3(2.0g), reaction, TLC tracing detections is stirred at room temperature.Reaction finishes, and is evaporated under reduced pressure away acetone, 150mL water is added, is extracted with ethyl acetate, merges organic phase, concentrated hydrochloric acid acidifying is added, absolute ethyl alcohol band water, obtains dark oil Shape thing, acetone recrystallization, crystal is separated out, is alkalized after filtering, obtains white solid (0.63g, yield 46.8%).Mp 87-88 ℃.MS(ESI):m/z(M+H)+269.8.1H NMR(300MHz,CDCl3) δ 8.67 (d, J=4.7Hz, 1H, ArH), 8.12 (d, J=9.2Hz, 1H, ArH), 7.52-7.30 (m, 8H, ArH), 5.21 (s, 2H, CH2).13C NMR(75MHz,CDCl3)δ 160.2,150.7,150.0,142.2,135.9,128.5,128.1,127.5,125.2,121.6,120.9,119.2, 108.7,70.3.
Embodiment 50：Prepare 4- chloro- 7- (4- fluorine benzyloxy) quinoline (compound 23h)
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (15ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), is stirred at room temperature 10min, then adds 4- fluorobenzyl chlorides (3.5mmol) and continues to react, TLC tracing detections. Reaction is finished, and reaction mixture is poured into water, and ethyl acetate extraction, merges organic phase, adds concentrated hydrochloric acid acidifying, absolute ethyl alcohol Band water, yellow oil is obtained, re-crystallizing in ethyl acetate, pale yellow crystals is separated out, is alkalized after filtering, obtain yellow solid (0.57g, yield 89.2%).Mp 98-99℃.MS(ESI):m/z(M+H)+287.9.1H NMR(300MHz,CDCl3)δ8.67 (d, J=4.8Hz, 1H, ArH), 8.12 (d, J=9.2Hz, 1H, ArH), 7.49-7.42 (m, 3H, ArH), 7.36-7.30 (m, 2H, ArH), 7.08 (t, J=8.7Hz, 2H, ArH), 5.17 (s, 2H, CH2).13C NMR(75MHz,CDCl3)δ162.4(d,J =246.4Hz), 159.9,150.6,150.0,142.2,131.7 (d, J=2.2Hz), 129.4 (d, J=8.1Hz), 125.2, (121.6,120.8,119.2,115.44 d, J=21.5Hz), 108.6,69.5.
Embodiment 50：Prepare 4- chloro- 7- (3- benzene ethyoxyl) quinoline (compound 23i)
The chloro- 7- oxyquinolines (0.36g, 2mmol) of 4-, DMF (10ml) and 60% are added in 100ml round-bottomed flask NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds 1- bromine 2- diphenylphosphino ethanes (3.5mmol) and continue to react, TLC tracking inspections Survey.Reaction is finished, and reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, nothing Aqueous sodium persulfate is dried, and is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=200/1), obtain light yellow solid Body (0.14g, yield 23.3%).Mp 84-85℃.MS(ESI):m/z(M+H)+283.8.1H NMR(300MHz,CDCl3)δ 8.64 (d, J=4.0Hz, 1H, ArH), 8.07 (d, J=9.1Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.36-7.19 (m, 7H, ArH), 4.34 (t, J=6.7Hz, 2H, OCH2CH2), 3.18 (t, J=6.7Hz, 2H, OCH2CH2).13CNMR(75MHz, CDCl3)δ160.1150.6,149.8,142.0,137.7,128.7,128.3,126.4,124.9,121.3,120.7, 118.9,108.1,68.7,35.4.
Embodiment 50：Prepare 4- chloro- 7- (3- phenylpropyl alcohols epoxide) quinoline (compound 23j)
The chloro- 7- oxyquinolines (0.45g, 2.5mmol) of 4- and DMF (15ml), room temperature are added in 100ml round-bottomed flask 10min is stirred, then adds 60%NaH (0.2g, 5mmol), 10min is stirred at room temperature, adds 1- bromine 3- phenyl-propanes (5mmol) Continue to react, TLC tracing detections.Reaction is finished, and reaction mixture is poured into water, and ethyl acetate extraction, is merged organic phase, is subtracted Pressure is concentrated to dryness, and obtains yellow oil, adds concentrated hydrochloric acid acidifying, white solid occurs, with 20mL acetone/petroleum ether=3：1 weight Crystallization, alkalization is used again after obtaining solid, obtains white crystal (0.03g, yield 53.6%).Mp 51-52℃.MS(ESI):m/z(M +H)+297.9.1H NMR(300MHz,CDCl3) δ 8.64 (d, J=4.3Hz, 1H, ArH), 8.08 (d, J=9.1Hz, 1H, ), ArH 7.36 (s, 1H, ArH), 7.33-7.15 (m, 7H, ArH), 4.10 (t, J=6.0Hz, 2H, OCH2CH2CH2),2.84(t, J=7.4Hz, 2H, OCH2CH2CH2),2.26–2.10(m,2H,OCH2CH2CH2).13C NMR(75MHz,CDCl3)δ (160.4150.6,149.8,142.0,140.9,128.2 C=2), 125.8,124.9,121.3,120.7,118.9,108.0, 67.2,32.1,30.5.
Synthetic route 8：
Embodiment 51：Prepare N1- (7- ethoxyquinoline -4- bases)-N2,N2- diethyl ethane -1,2- diamines (compounds 24a)
Compound 23a (0.35g, 1.7mmol) and N, N- diethyl ethylenediamine (4mL), heating are added in 100mL flasks Back flow reaction 3.5h, TLC tracing detection.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, wash, Saturated common salt is washed, and anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol= 100/1) light yellow solid (0.36g, yield 73.7%), is obtained.Mp 84-85℃.MS(ESI):m/z(M+H)+287.9.1H NMR (300MHz,CDCl3) δ 8.44 (d, J=5.2Hz, 1H, ArH), 7.61 (d, J=9.1Hz, 1H, ArH), 7.28 (s, 1H, )), ArH 7.04 (d, J=9.0Hz, 1H, ArH), 6.25 (d, J=5.3Hz, 1H, ArH), 5.98 (s, 1H, NH), 4.13 (q, J =6.9Hz, 2H, OCH2CH3), 3.20 (dd, J=10.1,5.1Hz, 2H, NHCH2CH2), 2.75 (t, J=5.8Hz, 2H, NHCH2CH2), 2.56 (q, J=7.0Hz, 4H, N (CH2CH3)2), 1.46 (t, J=6.9Hz, 1H, OCH2CH3), 1.04 (t, J= 7.1Hz,6H,N(CH2CH3)2).13C NMR(75MHz,CDCl3)δ159.2,151.1,150.0,149.7,120.6,116.9, 113.2,108.5,97.8,63.3,50.6,46.4,39.7,14.7,12.0.
Embodiment 52：Prepare N1 ,N1- diethyl-N2- (7- hexyloxies quinolyl-4) ethane -1,2- diamines (compounds 24b)
23c (0.53g, 2mmol) and N, N- diethyl ethylenediamine (4mL), heating reflux reaction are added in 100mL flasks 3.5h, TLC tracing detection.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain yellow Color solid (0.59g, yield 85.4%).Mp 92-93℃.MS(ESI):m/z(M+H)+344.0.1H NMR(300MHz, CDCl3) δ 8.43 (d, J=5.3Hz, 1H, ArH), 7.61 (d, J=9.1Hz, 1H, ArH), 7.28 (d, J=2.0Hz, 1H, ), ArH 7.04 (dd, J=9.0,2.2Hz, 1H, ArH), 6.26 (d, J=5.3Hz, 1H, ArH), 5.98 (s, 1H, NH), 4.06 (t, J=6.5Hz, 2H, OCH2(CH2)4CH3), 3.22 (dd, J=10.3,5.4Hz, 2H, NHCH2CH2), 2.77 (t, J= 5.8Hz,2H,NHCH2CH2), 2.57 (q, J=7.0Hz, 4H, N (CH2CH3)2),1.89-1.76(m,2H,OCH2CH2(CH2)3CH3),1.54-1.42(m,2H,O(CH2)2CH2(CH2)2CH3), 1.34 (d, J=3.5Hz, 4H, O (CH2)3(CH2)2CH3, 1.05 (t, J=7.1Hz, 6H, N (CH2CH3)2), 0.90 (t, J=6.5Hz, 3H, O (CH2)5CH3).13C NMR(75MHz, CDCl3)δ159.5,151.1,145.0,149.8,120.6,117.1,113.2,108.6,97.8,68.0,50.7,46.5, 39.8,31.6,29.1,25.8,22.6,14.1,12.1.
Embodiment 53：Prepare N1- (7- allyloxys quinolyl-4)-N2,N2- diethyl ethane -1,2- diamines (compounds 24c)
23d (0.33g, 1.5mmol) and N, N- diethyl ethylenediamine (4mL) are added in 100mL flasks, is heated to reflux anti- Answer 4h, TLC tracing detections.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain white Color solid (0.36g, yield 79.8%).Mp yellowoil.MS(ESI):m/z(M+H)+300.1.1H NMR(300MHz, CDCl3) δ 8.43 (d, J=5.3Hz, 1H, ArH), 7.62 (d, J=9.1Hz, 1H, ArH), 7.30 (d, J=2.1Hz, 1H, ), ArH 7.08 (dd, J=9.2,1.9Hz, 1H, ArH), 6.28 (d, J=5.3Hz, 1H, ArH), 6.09 (ddd, J=15.8, 10.5,5.2Hz,1H,CH2=CH), 5.97 (s, 1H, NH), 5.46 (d, J=17.2Hz, 1H, CH2=CH), 5.31 (d, J= 10.5Hz,1H,CH2=CH), 4.65 (d, J=5.0Hz, 2H, OCH2CH=CH2), 3.25 (dd, J=10.6,5.4Hz, 2H, NHCH2CH2), 2.80 (t, J=5.8Hz, 2H, NHCH2CH2), 2.59 (q, J=7.1Hz, 4H, (CH2CH3)2), 1.07 (t, J= 7.1Hz,6H,(CH2CH3)2).13C NMR(75MHz,CDCl3)δ158.4,150.4,149.5,149.3,132.2,120.8, 117.1,116.3,113.1,108.2,97.2,68.1,50.3,46.0,39.5,11.4.
Embodiment 54：Prepare N1,N1- diethyl-N2- (7- isopropoxies quinolyl-4) ethane -1,2- diamines (compounds 24d)
23e (0.20g, 0.9mmol) and N, N- diethyl ethylenediamine (4mL) are added in 100mL flasks, is heated to reflux anti- Answer 5h, TLC tracing detections.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain yellow Color grease (0.12g, yield 10.9%).Mp yellowoil.MS(ESI):m/z(M+H)+302.1.1H NMR(300MHz, CDCl3) δ 8.42 (d, J=5.3Hz, 1H, ArH), 7.61 (d, J=9.1Hz, 1H, ArH), 7.29 (d, J=2.0Hz, 1H, ), ArH 7.01 (dd, J=9.1,2.1Hz, 1H, ArH), 6.26 (d, J=5.3Hz, 1H, ArH), 5.99 (s, 1H, NH), 4.80- 4.62(m,1H,OCH(CH3)2), 3.24 (dd, J=10.5,5.3Hz, 2H, NHCH2CH2), 2.79 (t, J=5.9Hz, 2H, NHCH2CH2), 2.58 (q, J=7.1Hz, 4H, N (CH2CH3)2), 1.40 (d, J=6.0Hz, 6H, OCH (CH3)2),1.06(t,J =7.1Hz, 6H, N (CH2CH3)2).13C NMR(75MHz,CDCl3)δ158.2,150.7,149.8,149.7,120.8, 117.7,113.1,109.5,97.6,69.7,50.7,46.4439.8,21.8,12.0.
Embodiment 55：Prepare N1- (7- benyloxyquinoline -4- bases)-N2,N2- diethyl ethane -1,2- diamines (compounds 24e)
23g (0.12g, 0.4mmol) and N, N- diethyl ethylenediamine (2mL) are added in 100mL flasks, is heated to reflux anti- Answer 2.5h, TLC tracing detections.Reaction finishes, and adds absolute ethyl alcohol, and amine, silica gel column chromatography (flowing is distilled off in high-temperature pressure-reduction Phase：Methylene chloride/methanol=100/1), obtain light yellow solid (0.09g, yield 57.7%).Mp 93-94℃.MS(ESI):m/ z(M+H)+349.9.1H NMR(300MHz,CDCl3) δ 8.44 (d, J=4.7Hz, 1H, ArH), 7.63 (d, J=9.0Hz, 1H, ), ArH 7.47 (d, J=7.3Hz, 2H, ArH), 7.34 (dd, J=13.5,7.7Hz, 4H, ArH), 7.13 (d, J=9.0Hz, 1H, ArH), 6.28 (d, J=5.1Hz, 1H, ArH), 5.99 (s, 1H, NH), 5.17 (s, 2H, OCH2), 3.25 (d, J= 4.7Hz,2H,NHCH2CH2), 2.80 (t, J=5.4Hz, 2H, NHCH2CH2), 2.59 (q, J=6.8Hz, 4H, N (CH2CH3)2), 1.07 (t, J=6.9Hz, 6H, N (CH2CH3)2).13C NMR(75MHz,CDCl3)δ159.1,151.1,149.9,136.5, 128.4,127.9,127.5,120.9,117.1,113.6,109.6,109.2,105.24,98.0,70.0,50.8,46.5, 39.8,12.1.
Embodiment 56：Prepare N1,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) ethane -1,2- diamines (is changed Compound 24f)
23h (0.14g, 0.5mmol) and N, N- diethyl ethylenediamine (4mL) are added in 100mL flasks, is heated to reflux anti- Answer 3h, TLC tracing detections.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain white Color solid (0.10g, yield 55.9%).Mp 67-68℃.MS(ESI):m/z(M+H)+367.7.1H NMR(300MHz, CDCl3) δ 8.44 (d, J=5.3Hz, 1H, ArH), 7.63 (d, J=9.1Hz, 1H, ArH), 7.42 (dd, J=8.3,5.5Hz, 2H, ArH), 7.36 (d, J=2.4Hz, 1H, ArH), 7.10 (dd, J=9.1,2.5Hz, 1H, ArH), 7.04 (t, J=8.6Hz, 2H, ArH), 6.27 (d, J=5.3Hz, 1H, ArH), 5.99 (d, J=2.5Hz, 1H, NH), 5.11 (s, 2H, OCH2),3.23 (dd, J=10.4,5.4Hz, 2H, NHCH2CH2), 2.78 (t, J=5.9Hz, 2H, NHCH2CH2), 2.58 (q, J=7.1Hz, 4H,NCH2CH3), 1.06 (t, J=7.1Hz, 6H, NCH2CH3).13C NMR(75MHz,CDCl3) δ 162.32 (d, J= 246.0Hz), 159.0,151.0,149.9,149.8,132.3,129.32 (d, J=7.9Hz), 121.0,117.0,115.33 (d, J=21.5Hz), 113.6,109.1,98.0,69.3,50.8,46.6,39.9,12.1.
Synthetic route 9：
Embodiment 57：Prepare N1- (7- ethoxyquinoline -4- bases)-N2,N2- diethyl propane -1,2- diamines (compounds 25a)
23a (0.31g, 1.5mmol) and 3- diethyl amino propylamines (4mL), heating reflux reaction are added in 100mL flasks 4.5h, TLC tracing detection.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain yellow Color grease (0.34g, yield 75.2%).Mp yellowoil.MS(ESI):m/z(M+H)+302.1.1H NMR(400MHz, CDCl3) δ 8.41 (d, J=5.3Hz, 1H, ArH), 7.83 (s, 1H, NH), 7.64 (d, J=9.1Hz, 1H, ArH), 7.30 (s, 1H, ArH), 7.02 (d, J=9.1Hz, 1H, ArH), 6.23 (d, J=5.3Hz, 1H, ArH), 4.16 (q, J=6.9Hz, 2H, CH2CH3), 3.38 (d, J=4.5Hz, 2H, NCH2), 2.65 (dt, J=14.1,6.1Hz, 6H, CH2N(CH2CH3)2),1.97– 1.83(m,2H,NHCH2CH2CH2), 1.47 (t, J=6.8Hz, 3H, CH2CH3), 1.09 (t, J=7.0Hz, 6H, N (CH2CH3)2).13C NMR(100MHz,CDCl3)δ159.0,150.5,150.3,149.5,121.4,116.0,113.1, 107.8,96.5,62.9,52.5,46.4,43.5.
Embodiment 58：Prepare N1- (7- allyloxys quinolyl-4)-N2,N2- diethyl propane -1,2- diamines (compounds 25b)
23d (0.33g, 2mmol) and 3- diethyl amino propylamines (4mL), heating reflux reaction are added in 100mL flasks 2.5h, TLC tracing detection.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain yellow Color grease (0.15g, yield 31.9%).Mp yellow oil.MS(ESI):m/z(M+H)+313.9.1H NMR(300MHz, CDCl3) δ 8.40 (d, J=5.3Hz, 1H, ArH), 7.83 (s, 1H, NH), 7.64 (d, J=9.1Hz, 1H, ArH), 7.03 (dd, J=9.1,1.6Hz, 1H, ArH), 6.20 (d, J=5.4Hz, 1H, ArH), 6.08 (ddd, J=21.5,10.4,5.2Hz, 1H, CH=CH2), 5.45 (d, J=17.2Hz, 1H, CH=CH2), 5.29 (d, J=10.5Hz, 1H, CH=CH2), 4.63 (d, J= 5.2Hz,2H,OCH2), 3.34 (d, J=3.9Hz, 2H, NCH2(CH2)2), 2.61 (dd, J=13.9,6.7Hz, 6H, CH2N (CH2CH3)2),1.94–1.81(m,2H,NCH2CH2CH2), 1.07 (t, J=7.1Hz, 6H, N (CH2CH3)2).13C NMR (75MHz,CDCl3)δ158.8,151.0,150.5,149.8,132.8,121.7,117.7,116.5,113.6,108.7, 97.0,68.7,53.4,47.0,44.4,24.5,11.6.
Embodiment 59：Prepare N1,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) propane -1,2- diamines (is changed Compound 25c)
23h (0.29g, 1mmol) and 3- diethyl amino propylamines (4mL), heating reflux reaction are added in 100mL flasks 1.5h, TLC tracing detection.Reaction finishes, and adds about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography (mobile phase：Methylene chloride/methanol=100/1), obtain yellow Color grease (0.26g, yield 67.5%).Mp yellow oil.MS(ESI):m/z(M+H)+382.4.1H NMR(300MHz, CDCl3) δ 8.41 (d, J=5.2Hz, 1H, ArH), 7.83 (s, 1H, NH), 7.66 (d, J=9.1Hz, 1H, ArH), 7.45- 7.36 (m, 2H, ArH), 7.34 (s, 1H, ArH), 7.13-6.95 (m, 3H, ArH), 6.20 (d, J=5.1Hz, 1H, ArH), 5.08(s,2H,OCH2),3.32(s,2H,NHCH2(CH2)2),2.67-2.53(m,6H,CH2N(CH2CH3)2),1.84(s,2H, NHCH2CH2CH2), 1.06 (t, J=6.8Hz, 6H, N (CH2CH3)2).13C NMR(75MHz,CDCl3) δ 162.0 (d, J= 245.7Hz), 158.6,151.0,150.3,149.7,132.11 (d, J=2.0Hz), 129.0 (d, J=8.0Hz), 121.7, (116.1,115.0 d, J=21.4Hz), 113.6,108.8,96.8,68.9,53.0,46.7,44.1,24.3,11.4.
Experimental example 1：Anti tumor activity in vitro is tested
Oxoquinoline derivatives of the present invention are as the pharmacological research for preparing treating cancer medicinal usage.All tests Compound is prepared into hydrochloride form before the test, and positive control drug is used as using clinically conventional antineoplastic-cis-platinum Thing.
Human Laryngeal Cancer Cell (Hep-2), breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), liver are selected respectively Cancerous cell line (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer cell line (PC-3) etc. Cell line, tested using mtt assay.Specific method is as follows:Respectively by growth conditions are good, the cell in exponential phase Strain is with 5 × 104Individual/ml concentration is inoculated in 96 orifice plates, and 160 μ l are inoculated with per hole, 96 orifice plates then are placed in into 37 DEG C, containing 5%CO2 Incubator in cultivate 24 hours, abandon old liquid, change fresh medium, add the oxoquinoline derivatives of sterilization treatment, continue to train After supporting 48 hours, nutrient solution is discarded, 20ul MTT containing 5mg/ml RPMI-1640 nutrient solutions are added per hole, continues culture 4 hours, After careful removing supernatant, 200 μ l DMSO is added per hole, vibration about 10min dissolvings precipitate, and then detect OD values with ELIASA, Wavelength 490nm.The cell survival rate under each sample concentration is obtained with following formula：Survival rate %=sample sets mean OD value/control Group mean OD value × 100%.Drug concentration logarithm is mapped with cell survival rate, the IC of each sample is obtained by graphing method50Value, As a result see the table below.
Oxoquinoline derivatives extracorporeal anti-tumor result (IC of the present invention50,μM a)
a IC50Value represents to suppress the drug concentration required for 50% growth of tumour cell.
bTumor cell line includes human laryngeal cancer cell line (Hep-2), breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), liver cancer cell lines (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer is thin Born of the same parents are (PC-3).
cEach numerical value represents the average value of parallel test result three times in table.

Claims (5)

1. it is selected from following compound：
N1 , N1- diethyl-N2- (7- hexyloxies quinolyl-4) ethane -1,2- diamines,
N1- (7- benyloxyquinoline -4- bases)-N2,N2- diethyl ethane -1,2- diamines,
N1 ,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) ethane -1,2- diamines,
N1 ,N1- diethyl-N2- (7- (4- fluorine benzyloxy) quinolyl-4) propane -1,2- diamines,
And their pharmaceutically acceptable salt.
2. compound described in claim 1 or its pharmaceutically acceptable salt are being prepared for preventing or treating in the medicine of tumour Purposes.
3. purposes according to claim 2, described tumour is selected from：Melanoma, stomach cancer, lung cancer, breast cancer, kidney, liver cancer, Oral cavity epidermal carcinoma, cervical carcinoma, oophoroma, cancer of pancreas, prostate cancer, colon cancer, carcinoma of urinary bladder, head and neck neoplasm, nasopharyngeal carcinoma, skin Cancer, leukaemia.
4. purposes according to claim 3, the leukaemia is selected from ALL, chronic leukemia.
5. a kind of pharmaceutical composition, wherein containing compound described at least one claim 1 or its pharmaceutically acceptable salt, with And optional pharmaceutical carrier or excipient.
CN201510393896.9A 2012-12-12 2013-12-05 7-chloro-4-oxo-quinoline derivative with antitumor activity Active CN105017145B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510393896.9A CN105017145B (en) 2012-12-12 2013-12-05 7-chloro-4-oxo-quinoline derivative with antitumor activity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2012105329923 2012-12-12
CN201210532992 2012-12-12
CN201310652191.5A CN103864680B (en) 2012-12-12 2013-12-05 There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity
CN201510393896.9A CN105017145B (en) 2012-12-12 2013-12-05 7-chloro-4-oxo-quinoline derivative with antitumor activity

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201310652191.5A Division CN103864680B (en) 2012-12-12 2013-12-05 There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity

Publications (2)

Publication Number Publication Date
CN105017145A CN105017145A (en) 2015-11-04
CN105017145B true CN105017145B (en) 2017-12-05

Family

ID=50903751

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201310652191.5A Active CN103864680B (en) 2012-12-12 2013-12-05 There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity
CN201510393896.9A Active CN105017145B (en) 2012-12-12 2013-12-05 7-chloro-4-oxo-quinoline derivative with antitumor activity

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201310652191.5A Active CN103864680B (en) 2012-12-12 2013-12-05 There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity

Country Status (1)

Country Link
CN (2) CN103864680B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108892639B (en) * 2018-08-13 2021-05-14 云南民族大学 Efficient and environment-friendly method for preparing quinolone compounds
WO2020184578A1 (en) * 2019-03-11 2020-09-17 小胞体ストレス研究所株式会社 NOVEL elF2α PHOSPHORYLATION PROMOTER
CN116693452A (en) * 2023-05-24 2023-09-05 中山大学 Quinoline derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0786454A1 (en) * 1994-10-07 1997-07-30 Zenyaku Kogyo Kabushikikaisha Thioquinolone derivative
JP2006117555A (en) * 2004-10-20 2006-05-11 Kyorin Pharmaceut Co Ltd 1-trifluoromethyl-4-quinolonecarboxylic acid derivative
CN101440063A (en) * 2008-12-19 2009-05-27 重庆康乐制药有限公司 Preparation of piperaquini phosphatis

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8515209D0 (en) * 1985-06-15 1985-07-17 Boots Co Plc Therapeutic agents
GB9621757D0 (en) * 1996-10-18 1996-12-11 Ciba Geigy Ag Phenyl-substituted bicyclic heterocyclyl derivatives and their use
CN1091102C (en) * 1998-10-21 2002-09-18 中外合资通化茂祥制药有限公司 7-chloro-4-oxo-quinoline and its preparation method and novel use as medicine
FR2797444B1 (en) * 1999-08-13 2003-02-07 Lafon Labor PHARMACEUTICAL COMPOSITIONS COMPRISING 4-QUINOLONES

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0786454A1 (en) * 1994-10-07 1997-07-30 Zenyaku Kogyo Kabushikikaisha Thioquinolone derivative
JP2006117555A (en) * 2004-10-20 2006-05-11 Kyorin Pharmaceut Co Ltd 1-trifluoromethyl-4-quinolonecarboxylic acid derivative
CN101440063A (en) * 2008-12-19 2009-05-27 重庆康乐制药有限公司 Preparation of piperaquini phosphatis

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Acid catalyzed alcoholysis of 4,7-dichloroquinoline;Ned D. Heindel，等;《Journal of Heterocyclic Chemistry》;19691231;第6卷(第6期);第961页 *
Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer;Pei-Du Jiang,等;《Biomedicine & Pharmacotherapy》;20101231(第64期);第609-614页 *
Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells;Chuandong Fan，等;《Bioorganic & Medicinal Chemistry》;20060118(第14期);第3218-3222页 *
Microwave-assisted synthesis of 4-quinolylhydrazines followed by nickel boride reduction: a convenient approach to 4-aminoquinolines and derivatives;Sandra Gemma，等;《Tetrahedron Letters》;20080202(第49期);第2074-2077页 *
Structure-Activity Relationships in 4-Aminoquinoline Antiplasmodials. The Role of the Group at the 7-Position;Catherine H. Kaschula，等;《J. Med. Chem.》;20020629(第45期);第3531-3539页 *
Unusually high probability of second harmonic generation by some crystalline organic aldehydes;Hutchings, Michael G.等;《MCLC S&T, Section B: Nonlinear Optics》;19941231;第7卷(第1-2期);第157-166页 *

Also Published As

Publication number Publication date
CN103864680B (en) 2015-09-02
CN103864680A (en) 2014-06-18
CN105017145A (en) 2015-11-04

Similar Documents

Publication Publication Date Title
CA2736097C (en) Carbazole compounds for inhibition of nf-kb activity
CN105153122B (en) [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application
CN104530061B (en) Icotinib hydrochloride crystal forms, medicine composition and application of icotinib hydrochloride crystal forms
CN103694238B (en) NO donor type matrine derivative and preparation method and medical application thereof
CN102295642A (en) 2-aryl imidazo [1,2-a] pyridine-3-acetamide derivative and preparation method as well as application thereof
WO2013107164A1 (en) Novel indoleamine-2, 3-dioxygenase inhibitor, preparation method therefor and uses thereof
CN108864111A (en) A kind of Tr*ger ' s base class compound and the preparation method and application thereof containing benzimidazole
CN107417695B (en) Berberine derivatives, preparation method thereof, pharmaceutical composition and anti-tumor application thereof
CN105017145B (en) 7-chloro-4-oxo-quinoline derivative with antitumor activity
Jiang et al. Anti-angiogenic and anticancer effects of baicalein derivatives based on transgenic zebrafish model
CN106946760A (en) Derivatives of indirubin or pharmaceutically receptible salt are used for antineoplastic and preparation method
CN106810552A (en) Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof
CN105566305B (en) The polymorph and its preparation method and application of 4- (substituted anilinic) quinazoline derivant xylenesulfonate
CN106905319A (en) The preparation method of substitution benzene sulfonyl kuh-seng butane or its hydrochloride
CN106946868A (en) Nitric oxide donator type coumarin derivative, its preparation method and medical usage
CN111454229B (en) Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs
CN106565674A (en) Octahydrocyclopentano[c]pyrrole derivatives, and preparation methods and medicinal application thereof
CN102066362A (en) Dihydroindolinone derivatives
JP2010518173A (en) Salt form of 4-phenylaminoquinazoline derivative
CN111747921A (en) Preparation method and medical application of daphnetin derivative
CN109988110B (en) 4-phenoxy quinoline sulfonylurea compound, intermediate for synthesizing the compound and its preparation method and use
CN103804388B (en) 4 β-nitrogen substituted furan tertiary amines podophyllotoxin derivative and preparation method thereof and application
CN108409698B (en) RT/PR double-target HIV inhibitor and preparation method and application thereof
CN106349257B (en) The double B-carboline alkaloid compounds and its pharmaceutical applications that 3 piperazine bridgings connect
WO2008019572A1 (en) Meptazinol biligand derivatives and/or their salts, preparation method and uses thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant