CN109942499A - Quinazoline derivant and its preparation method and application - Google Patents
Quinazoline derivant and its preparation method and application Download PDFInfo
- Publication number
- CN109942499A CN109942499A CN201910249262.4A CN201910249262A CN109942499A CN 109942499 A CN109942499 A CN 109942499A CN 201910249262 A CN201910249262 A CN 201910249262A CN 109942499 A CN109942499 A CN 109942499A
- Authority
- CN
- China
- Prior art keywords
- compound
- amino
- methylethyl
- phenylamino
- preparation
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to quinazoline derivants and its preparation method and application.The quinazoline derivant has
Description
Technical field
The present invention relates to field of medicinal chemistry more particularly to quinazoline derivant and its preparation method and application.
Background technique
PBK/TOPK is that a kind of serine/threonine kinase of phosphorylation during mitosis and one are important
Endocellular signal molecule.Original research finds that PBK/TOPK can be in conjunction with PDZ structural domain, it can be with tumor suppressor gene hD1g, P53
Multiple molecules such as albumen and raf albumen, which combine, to play a role, moreover it is possible to MAPK (p38, the ERK, JNK) signal path in downstream is activated,
It plays an important role in tumour is formed.With deepening continuously of studying it and develop, discovery PBK/TOPK is in the normal tissue
It in low expression or does not express, and high expression is presented in Several Kinds of Malignancy cell, what it not only regulated and controled tumour cell has silk
Division and cell cycle, and the processes such as proliferation, migration, invasion and apoptosis for taking part in tumour cell.Therefore PBK/TOPK will
It is the potential target spot of an extraordinary cancer treatment drugs.
Currently, artificial synthesized PBK/TOPK inhibitor only has three categories, the first kind is 7- Hydroxy-benzoimidazol -4- first
Base ketones derivant represents drug as HI-TOPK-032.Second class is thieno [2,3-c] quinoline ketone derivative, represents medicine
Object is OTS514 and OTS964.Third major class is the proton pump inhibitor of old medicine newly, such as Pantoprazole and Iprazole.Although
PBK/TOPK inhibitor is in the preclinical study stage, but has all shown in cell and Transplanted tumor model test good
Anti-tumor effect.Selectively acting will become current in efficient, less toxic, high specificity the new type antineoplastic medicine of specific target spot
The important directions of anti-tumor drug research and development.
Summary of the invention
The invention proposes quinazoline derivants and its preparation method and application.
Quinazoline derivant proposed by the present invention, has the following structure formula:
In formula ,-R1Selected from 2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, 2- amino -1- Methylethyl, 1- acetamidoethyl, 1-
Amino-ethyl, (R) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (S) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (R) -2- amino -1- first
Base ethyl, two kinds of structural formulas of (S) -2- amino -1- Methylethyl, (R) -1- acetamidoethyl, (S) -1- acetamidoethyl,
(R) one of -1- amino-ethyl, (S) -1- amino-ethyl;-R2Selected from hexahydro piperidines propyl, nafoxidine propyl, dimethylamine
One of propyl, morpholine propyl, dibutyl amine propyl.
Further, the structural formula of the quinazoline derivant is selected from one of following structural formula:
The present invention also proposes a kind of preparation method of quinazoline derivant described in any of the above embodiments, comprising the following steps:
1) compound A1 and sodium hydroxide solution are subjected to neutralization reaction, obtain compound A2, the structure of the compound A1
Formula isThe structural formula of the compound A2 is-R3Selected from 2- amino -1- Methylethyl, (R) -2-
Amino -1- Methylethyl, (S) -2- amino -1- Methylethyl, 1- amino-ethyl, (R) -1- amino-ethyl, (S) -1- amino second
One of base;Later in methylene chloride by compound A2 dissolution, it is cooled to -5~0 DEG C, aceticanhydride solution is added dropwise and carries out
Acylation reaction, obtains compound A-13, and the structural formula of the compound A-13 is-R1Selected from 2- acetylaminohydroxyphenylarsonic acid 1- methyl second
Base, 2- amino -1- Methylethyl, 1- acetamidoethyl, 1- amino-ethyl, (R) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (S) -
2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (R) -2- amino -1- Methylethyl, (S) -2- amino -1- Methylethyl, (R) -1- acetyl
One of amino-ethyl, (S) -1- acetamidoethyl, (R) -1- amino-ethyl, (S) -1- amino-ethyl;
2) it in methylene chloride by compound A-13 dissolution, is cooled to -5~0 DEG C, mixed acid solution is slowly added dropwise and carries out nitre
Change reaction, obtains compound A4, the structural formula of the compound A4 isThe mixed acid solution is preferably nitration mixture
The acid solution that 98% sulfuric acid and 68% nitric acid are mixed with volume ratio for 1.2:1;
3) nitro on the compound A4 phenyl ring is reduced into amino, obtains compound A-45, the knot of the compound A-45
Structure formula isSpecifically, using active carbon, Iron(III) chloride hexahydrate, dehydrated alcohol and the compound A4 into
Row nitro restores to obtain the compound A-45;
4) substitution reaction is occurred into for compound B3 and the compound A-45 and obtains compound A6, the structural formula of the compound A6
For, the structural formula of the compound B3 is
5) hydrolysis is occurred into for the compound A6 and ammonium hydroxide, obtains compound A7, the structural formula of the compound A7 is
6) substitution reaction is occurred into for the compound A7 and compound M, compound A-28 is obtained, wherein the compound M is
Contain-R2Group ,-R2Selected from hexahydro piperidines propyl, nafoxidine propyl, dimethylamine propyl, morpholine propyl, dibutyl amine propyl
One of, the structural formula of the compound A-28 is
Preferably, before step 4), further include the preparation of the compound B3: compound B-11 and aceticanhydride are acylated
Reaction, obtains compound B2, the structural formula of the compound B-11 isThe structural formula of the compound B2 isHalogenation is occurred into for the compound B2 and thionyl chloride, obtains the compound B3.Preferably,
The compound B-11 is mixed with acetic anhydride, pyridine, DMAP and 4-dimethylaminopyridine occur the acylation reaction obtain it is described
Compound B2;Halogenation is occurred into for the compound B2 and thionyl chloride and generates the compound B3.
Preferably, the dosage molar ratio of compound A2 described in step 1) and the aceticanhydride in the aceticanhydride solution is 1:1.2
~1.5, the reaction time is 8~10h.
Preferably, nitration mixture used in nitration reaction described in step 2) is 98% sulfuric acid and 68% nitric acid with volume ratio
The acid solution that 1.2:1 is mixed, temperature control -5~0 DEG C.
Preferably, the nitro on the compound A4 phenyl ring is reduced into the method for amino using iron powder reducing in step 3)
One of method, hydrazine hydrate reduction method, hydrosulfurous acid sodium reduction, two hydrated stannous chloride reduction methods, preferably hydrazine hydrate are also
Former method;The dosage molar ratio of the compound A4 and 80% hydrazine hydrate is 1:2.5~4.0,75~88 DEG C of reaction temperature, when reaction
Between 4~6h.
Preferably, the compound B-11 and the compound B-11 and aceticanhydride occur the reaction temperature of acylation reaction be 95~
100 DEG C, the time is 5~8h.
Preferably, the dosage molar ratio that substitution reaction occurs for compound A-45 described in step 4) and the compound B3 is 1:
0.8~0.9, reaction temperature is 90 DEG C~100 DEG C, 4~6h of reaction time.
Preferably, the molar ratio of the compound A6 described in step 5) and the ammonium hydroxide is 1:4~7, reaction temperature 60
DEG C~70 DEG C, 3~5h of reaction time.
Preferably, the dosage molar ratio that substitution reaction occurs for compound A7 described in step 6) and the compound M is 1:
1.2~1.5;90~95 DEG C of reaction temperature;5~8h of reaction time.
In addition, the invention also provides quinazoline derivants described above to prepare answering in PBK/TOPK inhibitor
With.
In addition, the invention also provides quinazoline derivants described above to prepare the application in anticancer drug.
Preferably, the anticancer drug includes anti-lung-cancer medicament and anti-breast cancer medicines.
The beneficial effect of the present invention compared with the prior art includes: quinazoline derivant proposed by the present invention with Gefitinib
For positive control, the results showed that have good activity compared with Gefitinib;Compared with lead compound OTS514, active phase
When, for PBK/TOPK inhibitor be further transformed and find new anti-tumor drug candidate it is with higher reference and reference
Value.
The embodiment of the invention also provides a kind of preparation methods of quinazoline derivant, use quinazoline skeleton, pass through
Related group is introduced on quinazoline ring, obtains a series of compounds with anti-tumor activity.This method can high-efficiency high-quality
Ground obtains a variety of quinazoline derivants, simple to operate, not high to equipment requirement, is suitble to large-scale production and application.
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, below to specific reality of the invention
The mode of applying is described in detail.In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention.But
The invention can be embodied in many other ways as described herein, and those skilled in the art can be without prejudice to this hair
Similar improvement is done in the case where bright intension, therefore the present invention is not limited to the specific embodiments disclosed below.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.The person that is not specified actual conditions in embodiment, according to normal conditions or
The condition that manufacturer suggests carries out.Reagents or instruments used without specified manufacturer is that can be obtained by commercially available purchase
Conventional products.
Present embodiment proposes quinazoline derivant, has the following structure formula:
In formula ,-R1Selected from 2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, 2- amino -1- Methylethyl, 1- acetamidoethyl, 1-
Amino-ethyl, (R) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (S) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (R) -2- amino -1- first
Base ethyl, two kinds of structural formulas of (S) -2- amino -1- Methylethyl, (R) -1- acetamidoethyl, (S) -1- acetamidoethyl,
(R) one of -1- amino-ethyl, (S) -1- amino-ethyl;-R2Selected from hexahydro piperidines propyl, nafoxidine propyl, dimethylamine
One of propyl, morpholine propyl, dibutyl amine propyl.The structural formula of quinazoline derivant can choose 60 kinds of changes in structure above
Any one in object is closed, for the preparation method and performance for further illustrating quinazoline derivant proposed by the present invention, is now enumerated
The preparation method and performance study of partial structural formula therein are described in detail.
7- methoxyl group -6- acetoxyl group -4- chloro-quinazoline (i.e. compound B3) in this specific embodiment mode by with
The preparation of lower section method
By 6- hydroxyl -7- methoxyl group -4- ketone quinazoline (20g, 0.11mol, i.e. compound B-11), acetic anhydride (150mL,
It 1.6mol) is added sequentially in the round-bottomed flask of 500mL with pyridine (20mL, 0.25mol), is warming up to 100 DEG C of back flow reaction 1h
Afterwards, 4-dimethylaminopyridine (0.9g, 0.0073mol) is added, the reaction was continued 5h stops reaction, removes acetic anhydride under reduced pressure, to anti-
It answers and cold saturated sodium carbonate solution (500mL) stirring is added in liquid, filter, filter cake is transferred in round-bottomed flask and a large amount of ice water are added
Stirring filters, and filter cake is washed with distilled water until PH=7, and drying obtains white-yellowish solid (i.e. compound B2).By itself and chlorination
Sulfoxide (190mL, 2.0mol) is added sequentially in the three neck round bottom flask of 500mL, is warming up to 80 DEG C of back flow reaction 20min, from
N,N-Dimethylformamide (4.4mL, 0.52eq) is slowly added drop-wise in reaction solution by constant pressure funnel.6h is reacted, is stopped anti-
It answers, it is cooling, thionyl chloride is recovered under reduced pressure, suitable toluene stirring is added, toluene is recovered under reduced pressure, ice water is added into reactant
After (250mL) stir about 1h, methylene chloride (120mL*2) is extracted, and separates organic layer, water (80mL*2) washing, anhydrous sodium sulfate
It is dry, it removes methylene chloride under reduced pressure, obtains pale solid 21.5g, yield: 81.9%.
Embodiment 1
4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) third oxygen
Base) quinazoline preparation
(1) preparation of N- (2- phenyl propyl) acetamide (i.e. a kind of compound A-13)
2- phenyl -1- propylamin hydrochloride (20g, 0.118mol, i.e., a kind of compound A1) is dissolved in distilled water (20mL), is added
Enter sodium hydroxide solution (5.6g, 0.140mol), stirring at normal temperature reacts 30min, has yellow oil generation in the process, adds
Enter ethyl acetate (100mL*3) extraction, separates organic layer, water (100mL*2) washing, anhydrous sodium sulfate is dry, and second is recovered under reduced pressure
Acetoacetic ester obtains light yellow oil (i.e. a kind of compound A2).It is dissolved in methylene chloride (80mL), adds to the circle of 250mL
In the flask of bottom, it is placed in low temperature reaction vessel, acetic anhydride (12.8mL, 0.135mol) is dissolved in methylene chloride (30mL), and 0 DEG C of temperature control is slowly
It is added dropwise in round-bottomed flask, continues to be stirred to react 30min after dripping off, then be placed in and reaction 8h is stirred at room temperature, TLC detects fully reacting
Afterwards, stop reaction.Methylene chloride (70mL) is added into reaction solution and 2%NaOH solution (100mL) stirs 10min, has separated
Machine layer, water (100mL*2) washing, anhydrous sodium sulfate is dry, and methylene chloride is recovered under reduced pressure, obtains pale yellow oily liquid 18.0g, receives
Rate: 86.9%.
(2) preparation of N- [2- (4- nitrobenzophenone) propyl] acetamide (i.e. a kind of compound A4)
N- (2- phenyl propyl) acetamide (18.0g, 0.101mol) is placed in -5 DEG C of low temperature reaction vessel, is dripped from constant pressure
Liquid funnel is slowly added to 98% sulfuric acid of nitration mixture (12.2mL) and 68% nitric acid (10.1mL), and adjusts rate of addition, is added dropwise
Afterwards, it is stirred to react 1h, is taken out, the anti-18h of stirring at normal temperature is placed in, after TLC detects fully reacting, stops reaction.Reaction solution is poured into
In ice water, stirring, methylene chloride (30mL*3) is extracted, and separates organic layer, and anhydrous sodium sulfate is dry, removes methylene chloride under reduced pressure,
Yellow solid product 16.0g is obtained, yield: 70.9%.
(3) preparation of N- [2- (4- aminophenyl) propyl] acetamide (i.e. a kind of compound A-45)
By N- [2- (4- nitrobenzophenone) propyl] acetamide (6.0g, 0.027mol), active carbon (0.50g, 0.042mol),
Iron(III) chloride hexahydrate (0.23g, 0.001mol), dehydrated alcohol (60mL) are sequentially added equipped with constant pressure funnel, drying tube
In the 250mL there-necked flask of device.80 DEG C of back flow reactions are warming up to, 80% hydrazine hydrate is slowly added dropwise from constant pressure funnel
(4.1mL, 0.069mol) controls rate of titration, and about 30min is dripped off, and after reacting 5h, filters while hot, removes dehydrated alcohol under reduced pressure,
Methylene chloride (30mL*3) extracts, and anhydrous sodium sulfate is dry, removes methylene chloride under reduced pressure, obtains crude product column chromatography purifying (acetic acid
Ethyl ester: petroleum ether=4:1), 3.8g yellow oil is obtained, yield: 73.1%.
(4) 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline (i.e. one
Kind of compound A6) preparation
N- [2- (4- aminophenyl) propyl] acetamide (5.0g, 0.026mol), isopropanol (30mL) are added sequentially to
In the round-bottomed flask of 100mL, 7- methoxyl group -6- acetoxyl group -4- chloro-quinazoline (5.9g, 0.023mol) is added.It is warming up to
90 DEG C of back flow reaction 3h, after TLC detects fully reacting, stop reaction, filter, and filter cake is washed for several times with isopropanol, and drying obtains light
Yellow solid 8.0g, yield: 75.3%.
(5) 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (i.e. a kind ofization
Close object A7) preparation
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline (5.0g,
0.012mol), methanol (30mL), ammonium hydroxide (3.5mL, 0.091mol) are added sequentially in the round-bottomed flask of 100mL, are warming up to 65
DEG C back flow reaction 3h after TLC detects fully reacting, stops reaction, cooling, removes methanol under reduced pressure, obtain after yellow oil plus
Enter acetone (15mL), is warming up to 65 DEG C of reflux until there is white solid, stops reaction, filtering, filter cake acetone replaces with water
Washing, obtains white-yellowish solid 4.0g, yield: 88.9%.
(6) 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
Preparation
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (1g,
0.0027mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.57g, 0.0041mol), 1,3- bromo-chloropropane (0.3mL,
It 0.0032mol) is added sequentially in the round-bottomed flask of 100mL, is warming up to 75 DEG C of back flow reaction 5h, after TLC detects fully reacting,
Stop reaction, add water 50mL, stirring has solid precipitation, filters to obtain crude product, and acetone recrystallization obtains yellow solid 1.0g, receives
Rate: 82.7%.
(7) 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) third
Oxygroup) quinazoline preparation
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
(0.8g, 0.0018mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.38g, 0.0027mol), hexahydro piperidines
(0.20mL, 0.0022mol) is added sequentially in the round-bottomed flask of 100mL.It is anti-to be warming up to 90 DEG C of back flow reaction 5h, TLC detections
After answering completely, stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in
Acetone is slowly added dropwise hydrochloric acid stirring until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains faint yellow solid
0.56g, yield: 62.9%.168.9~172.1 DEG C of fusing point (mp).
It in other embodiments, can also be by by 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -
The compound of 7- methoxyquinazoline hydrochloride and N- (3- chloropropyl) piperidines directly occurs substitution reaction and generates 4- [4- (2- acetylaminohydroxyphenylarsonic acid
1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) propoxyl group) quinazoline (i.e. a kind of compound A-28).
Embodiment 2
4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base) third oxygen
Base) quinazoline preparation
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
(0.8g, 0.0018mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.38g, 0.0027mol), nafoxidine
(0.18mL, 0.0022mol) is added sequentially in the round-bottomed flask of 100mL.It is anti-to be warming up to 90 DEG C of back flow reaction 5h, TLC detections
After answering completely, stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in
Acetone is slowly added dropwise hydrochloric acid stirring until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains faint yellow solid
0.48g, yield: 55.8%.161.9~164.2 DEG C of mp.
It in other embodiments, can also be by by 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -
The compound of 7- methoxyquinazoline hydrochloride and 1- (3- chloropropyl) pyrrolidines directly occurs substitution reaction and generates 4- [4- (2- acetyl ammonia
Base -1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base) propoxyl group) quinazoline (i.e. a kind of compound
A8)。
Embodiment 3
4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dimethylamino) propoxyl group) quinoline
The preparation of oxazoline
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g,
0.0022mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N, N- dimethyl -3- chlorine propylamine
(0.34mL, 0.0026mol) is added sequentially in the round-bottomed flask of 100mL.It is anti-to be warming up to 90 DEG C of back flow reaction 5h, TLC detections
After answering completely, stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in
Acetone is slowly added dropwise hydrochloric acid stirring until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains faint yellow solid
0.62g, yield: 62.6%.Mp137.2~139.6 DEG C.
Embodiment 4
4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) propoxyl group) quinoline
The preparation of oxazoline
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g,
0.0022mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N- (3- chloropropyl)-morpholine
(0.40mL, 0.0026mol) is added sequentially in the round-bottomed flask of 100mL.It is anti-to be warming up to 90 DEG C of back flow reaction 5h, TLC detections
After answering completely, stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in
Acetone is slowly added dropwise hydrochloric acid stirring until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains faint yellow solid
0.85g, yield: 76.6%.Mp199.5~212.7 DEG C.
Embodiment 5
4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinoline
The preparation of oxazoline
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g,
0.0022mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N- (3- chloropropyl)-dibutyl
Amine (0.60mL, 0.0026mol) is added sequentially in the round-bottomed flask of 100mL.It is warming up to 90 DEG C of back flow reaction 5h, TLC detections
After fully reacting, stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is molten
In acetone, hydrochloric acid stirring is slowly added dropwise until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains faint yellow solid
0.93g, yield: 77.8%.Mp155.4~157.9 DEG C.
Embodiment 6
4- [4- (2- amino -1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
Preparation
By 4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group)
Quinazoline (0.1g, 0.0002mol) and 1N HCl (3mL) are added sequentially in the round-bottomed flask of 100mL.It is warming up to 95 DEG C of reflux
48h is reacted, after HPLC monitor and detection fully reacting, stops reaction.Vacuum distillation, mother liquor are repeatedly washed with a small amount of dehydrated alcohol,
Continue to remove dehydrated alcohol under reduced pressure, is dried in vacuo to obtain white-yellowish solid 0.07g, yield: 77.8%.Mp120.5~123.1 DEG C.
Embodiment 7
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl)
Propoxyl group) quinazoline preparation
(1) preparation of (R)-N- (2- phenyl propyl) acetamide
Step (1) 2- phenyl -1- propylamin hydrochloride in embodiment 1 is replaced with into (R) -2- phenyl -1- propylamin hydrochloride, it should
Other reaction conditions of step are identical as (1) the step of embodiment 1, obtain pale yellow oily liquid, yield: 85.2%.
(2) preparation of (R)-N- [2- (4- nitrobenzophenone) propyl] acetamide
Step (2) N- (2- phenyl propyl) acetamide in embodiment 1 is replaced with into (R)-N- (2- phenyl propyl) acetamide,
Other reaction conditions of the step are identical as (2) the step of embodiment 1, obtain yellow solid product, yield: 73.1%.
(3) preparation of (R)-N- [2- (4- aminophenyl) propyl] acetamide
Step (3) N- in embodiment 1 [2- (4- nitrobenzophenone) propyl] acetamide is replaced with into (R)-N- [2- (4- nitro
Phenyl) propyl] acetamide, other reaction conditions of the step are identical as (3) the step of embodiment 1, obtain yellow oil, receive
Rate: 69.9%.
(4) (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline
Preparation
Step (4) N- in embodiment 1 [2- (4- aminophenyl) propyl] acetamide is replaced with into (R)-N- [2- (4- amino
Phenyl) propyl] acetamide, other reaction conditions of the step are identical as (4) the step of embodiment 1, obtain faint yellow solid, receive
Rate: 78.8%.
(5) system of (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
It is standby
By step (5) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetyl
Oxygroup quinazoline replaces with (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinoline
Other reaction conditions of oxazoline, the step are identical as (5) the step of embodiment 1, obtain white-yellowish solid, yield: 92.5%.
(6) (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline
The preparation of oxazoline
By step (6) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyl group
Quinazoline replaces with (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, should
Other reaction conditions of step are identical as (6) the step of embodiment 1, obtain yellow solid, yield: 80.5%.
(7) (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidines
Base) propoxyl group) quinazoline preparation
By (7) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chlorine third
Oxygroup) quinazoline replaces with (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- chlorine
Base) quinazoline, other reaction conditions of the step are identical as (7) the step of embodiment 1, faint yellow solid is obtained, yield:
60.8%.177.9~179.1 DEG C of mp.
Embodiment 8
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base)
Propoxyl group) quinazoline preparation
By 4- in embodiment 2 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- chlorine
Base) quinazoline replaces with (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- chlorine
Base) quinazoline, other reaction conditions and step are same as Example 2, obtain faint yellow solid, yield: 53.2%.Mp 164.0~
165.2℃。
Embodiment 9
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dimethylamino)
Base) quinazoline preparation
By 4- in embodiment 3 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 3, obtain light yellow oil, yield: 60.0%.
Embodiment 10
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) third oxygen
Base) quinazoline preparation
By 4- in embodiment 4 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 4, obtain pale solid, yield: 73.5%.169.0~171.0 DEG C of mp.
Embodiment 11
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dibutyl amino)
Base) quinazoline preparation
By 4- in embodiment 5 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 5, obtain pale solid, yield: 75.5%.148.0~149.0 DEG C of mp.
Embodiment 12
(R) -4- [4- (2- amino -1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinoline
The preparation of oxazoline
By 4- in embodiment 6 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amine
Base) propoxyl group) quinazoline replaces with (R) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3-
(dibutyl amino) propoxyl group) quinazoline, other reaction conditions and step are same as Example 6, faint yellow solid is obtained, yield:
73.8%.121.4~122.9 DEG C of mp.
Embodiment 13
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl)
Propoxyl group) quinazoline preparation
(1) preparation of (S)-N- (2- phenyl propyl) acetamide
(1) 2- phenyl -1- propylamin hydrochloride in embodiment 1 is replaced with into (S) -2- phenyl -1- propylamin hydrochloride, other are anti-
The step of answering condition and embodiment 1 (1), obtains pale yellow oily liquid, yield: 82.5%.
(2) preparation of (S)-N- [2- (4- nitrobenzophenone) propyl] acetamide
(2) N- (2- phenyl propyl) acetamide in embodiment 1 is replaced with into (S)-N- (2- phenyl propyl) acetamide, other
The step of reaction condition and embodiment 1 (2), yellow solid product is obtained, yield: 69.9%.
(3) preparation of (S)-N- [2- (4- aminophenyl) propyl] acetamide
(3) N- in embodiment 1 [2- (4- nitrobenzophenone) propyl] acetamide is replaced with into (S)-N- [2- (4- nitrobenzophenone)
Propyl] acetamide, other reaction conditions and the step of embodiment 1 (3) obtain yellow oil, yield 65.0%.
(4) (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline
Preparation
(4) N- in embodiment 1 [2- (4- aminophenyl) propyl] acetamide is replaced with into (S)-N- [2- (4- aminophenyl)
Propyl] acetamide, other reaction conditions are identical as (4) the step of embodiment 1, obtain faint yellow solid, yield: 73.8%.
(5) system of (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
It is standby
By (5) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group
Quinazoline replaces with (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinoline azoles
The step of quinoline, other reaction conditions and embodiment 1 (5), white-yellowish solid is obtained, yield: 87.0%.
(6) (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline
The preparation of oxazoline
By (6) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyl group quinoline azoles
Quinoline replaces with (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other are anti-
The step of answering condition and embodiment 1 (6), obtains yellow solid, yield: 83.5%.
(7) (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidines
Base) propoxyl group) quinazoline preparation
By (7) 4- in embodiment 1 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- chlorine third
Oxygroup) quinazoline replaces with (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- chlorine
Base) quinazoline, other reaction conditions and the step of embodiment 1 (7) obtain faint yellow solid, yield: 58.0%.Mp 160.2~
163.3℃。
Embodiment 14
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base)
Propoxyl group) quinazoline preparation
By 4- in embodiment 2 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- chlorine
Base) quinazoline replaces with (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- chlorine
Base) quinazoline, other reaction conditions and step are same as Example 2, obtain faint yellow solid, yield: 57.0%.Mp 153.1~
154.3℃。
Embodiment 15
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dimethylamino)
Base) quinazoline preparation
By 4- in embodiment 3 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 3, obtain light yellow oil, yield: 65%.
Embodiment 16
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) third oxygen
Base) quinazoline preparation
By 4- in embodiment 4 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 4, obtain white solid, yield: 70.2%.168.4~170.0 DEG C of mp.
Embodiment 17
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dibutyl amino)
Base) quinazoline preparation
By 4- in embodiment 5 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
(S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with, other reactions
Condition and step are same as Example 5, obtain pale solid, yield: 76.0%.155.4~156.8 DEG C of mp.
Embodiment 18
(S) -4- [4- (2- amino -1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinoline
The preparation of oxazoline
By 4- in embodiment 6 [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amine
Base) propoxyl group) quinazoline replaces with (S) -4- [4- (2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl) phenylamino] -7- methoxyl group -6- (3-
(dibutyl amino) propoxyl group) quinazoline, other reaction conditions and step are same as Example 6, faint yellow solid is obtained, yield:
70.0%.119.9~120.1 DEG C of mp.
Embodiment 19
4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) propoxyl group) quinoline azoles
The preparation of quinoline
(1) preparation of N- [1- (4- nitrobenzophenone) ethyl] acetamide
1- phenyl ethylamine (20g, 0.165mol), methylene chloride (80mL) are added sequentially in the round-bottomed flask of 250mL, set
In low temperature reaction vessel, acetic anhydride (20mL, 0.196mol) is dissolved in methylene chloride (30mL), and 0 DEG C of temperature control is slowly added dropwise to round bottom burning
In bottle, continue to be stirred to react 30min after dripping off, then be placed in and reaction 8h is stirred at room temperature, after TLC detects fully reacting, stops reaction.
Methylene chloride (70mL) is added into reaction solution and 2%NaOH solution (100mL) stirs 10min, separates organic layer, water
(100mL*2) washing, anhydrous sodium sulfate is dry, and methylene chloride is recovered under reduced pressure, obtains white solid 24g.In -5 DEG C of low-temp reaction
In slots, 98% sulfuric acid of nitration mixture (17.8mL) and 68% nitric acid (15.0mL) are prepared, white solid is slowly added to, is stirred to react 1h,
It takes out, is placed in the anti-18h of stirring at normal temperature, after TLC detects fully reacting, stop reaction.Reaction solution is poured into ice water, is filtered, filter
Cake is washed with a large amount of water, obtains white-yellowish solid product 23.5g, yield: 68.3%.
(2) preparation of N- [1- (4- aminophenyl) ethyl] acetamide
By N- [1- (4- nitrobenzophenone) ethyl] acetamide (6.0g, 0.029mol), active carbon (1.16g, 0.097mol),
Iron(III) chloride hexahydrate (0.20g, 0.001mol), dehydrated alcohol (60mL) are sequentially added equipped with constant pressure funnel, drying tube
In the 250mL there-necked flask of device.80 DEG C of back flow reactions are warming up to, 80% hydrazine hydrate is slowly added dropwise from constant pressure funnel
(5.4mL, 0.108mol) controls rate of titration, and about 30min is dripped off, and after reacting 5h, filters while hot, removes dehydrated alcohol under reduced pressure,
Methylene chloride (30mL*3) extracts, and separates organic layer, and anhydrous sodium sulfate is dry, removes methylene chloride under reduced pressure, obtains 4.2g yellow
Grease, yield: 82.4%.
(3) preparation of 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline
N- [1- (4- aminophenyl) ethyl] acetamide (4.2g, 0.024mol), isopropanol (40mL) are added sequentially to
In the round-bottomed flask of 100mL, 7- methoxyl group -6- acetoxyl group -4- chloro-quinazoline (5.3g, 0.021mol) is added.It is warming up to
90 DEG C of back flow reaction 3h, after TLC detects fully reacting, stop reaction, filter, and filter cake is washed for several times with isopropanol, and drying obtains light
Yellow solid 6.8g, yield: 73.1%.
(4) preparation of 4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
By 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline (4g,
0.010mol), methanol (30mL), ammonium hydroxide (2.8mL, 0.073mol) are added sequentially in the round-bottomed flask of 100mL, are warming up to 65
DEG C back flow reaction 3h after TLC detects fully reacting, stops reaction, and cooling, filtering, filter cake is washed with isopropanol, obtains white solid
3.1g, yield: 86.1%.
(5) preparation of 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
By 4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (1g, 0.0028mol), N,
Dinethylformamide (10mL), potassium carbonate (0.57g, 0.0041mol), 1,3- bromo-chloropropane (0.3mL, 0.0032mol) according to
It is secondary to be added in the round-bottomed flask of 100mL, 75 DEG C of back flow reaction 5h are warming up to, after TLC detects fully reacting, stops reaction, adds
Water 50mL, stirring have solid precipitation, filter to obtain crude product, acetone recrystallization obtains yellow solid 0.9g, yield: 75%.
(6) 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) propoxyl group) quinoline
The preparation of oxazoline
By 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline (0.8g,
0.002mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.39g, 0.0028mol), hexahydro piperidines (0.22mL,
It 0.0024mol) is added sequentially in the round-bottomed flask of 100mL.90 DEG C of back flow reaction 6h are warming up to, after TLC detects fully reacting,
Stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in acetone, slowly
Hydrochloric acid stirring is added dropwise until there is solid appearance, suction filtration, a small amount of acetone washing of filter cake obtains faint yellow solid 0.52g, yield:
58.4%.129.1~130.9 DEG C of mp.
Embodiment 20
4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base) propoxyl group) quinoline azoles
The preparation of quinoline
By 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline (0.8g,
0.002mol), n,N-Dimethylformamide (10mL), potassium carbonate (0.39g, 0.0028mol), nafoxidine (0.19mL,
It 0.0022mol) is added sequentially in the round-bottomed flask of 100mL.90 DEG C of back flow reaction 6h are warming up to, after TLC detects fully reacting,
Stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in acetone, slowly
Hydrochloric acid stirring is added dropwise until there is solid appearance, suction filtration, a small amount of acetone washing of filter cake obtains faint yellow solid 0.42g, yield:
48.3%.132.5~134.7 DEG C of mp.
Embodiment 21
4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dimethylamino) propoxyl group) quinazoline
Preparation
By 4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g, 0.0023mol),
N,N-Dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N, N- dimethyl -3- chlorine propylamine (0.34mL,
It 0.0026mol) is added sequentially in the round-bottomed flask of 100mL.90 DEG C of back flow reaction 6h are warming up to, after TLC detects fully reacting,
Stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in acetone, slowly
Hydrochloric acid stirring is added dropwise until there is solid appearance, filters, a small amount of acetone washing of filter cake obtains light yellow oil 0.65g, receives
Rate: 65.7%.
Embodiment 22
4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) propoxyl group) quinazoline
Preparation
By 4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g, 0.0023mol),
N,N-Dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N- (3- chloropropyl)-morpholine (0.43mL,
It 0.0025mol) is added sequentially in the round-bottomed flask of 100mL.90 DEG C of back flow reaction 6h are warming up to, after TLC detects fully reacting,
Stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in acetone, slowly
Hydrochloric acid stirring is added dropwise until there is solid appearance, suction filtration, a small amount of acetone washing of filter cake obtains pale solid 0.79g, yield:
71.8%.185.0~188.5 DEG C of mp.
Embodiment 23
4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
Preparation
By 4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride (0.8g, 0.0023mol),
N,N-Dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N- (3- chloropropyl)-dibutylamine (0.63mL,
It 0.0028mol) is added sequentially in the round-bottomed flask of 100mL.90 DEG C of back flow reaction 6h are warming up to, after TLC detects fully reacting,
Stop reaction.Add water 50mL, stirring has solid precipitation, filters to obtain crude product.At room temperature, crude product is dissolved in acetone, slowly
Hydrochloric acid stirring is added dropwise until there is solid appearance, suction filtration, a small amount of acetone washing of filter cake obtains pale solid 0.72g, yield:
60%.165.4~167.7 DEG C of mp.
Embodiment 24
The preparation of 4- [4- (1- amino-ethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
By 4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
(0.1g, 0.0002mol) and 1N HCl (3mL) are added sequentially in the round-bottomed flask of 100mL.It is warming up to 95 DEG C of back flow reactions
After 48h, HPLC monitor and detection fully reacting, stop reaction.Vacuum distillation, mother liquor are repeatedly washed with a small amount of dehydrated alcohol, are continued
It removes dehydrated alcohol under reduced pressure, is dried in vacuo to obtain white-yellowish solid 0.06g, yield: 66.7%.Mp126.7~127.9 DEG C.
Embodiment 25
(R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) propoxyl group)
The preparation of quinazoline
(1) preparation of (R)-N- [1- (4- nitrobenzophenone) ethyl] acetamide
Step (1) 1- phenyl ethylamine in embodiment 19 is replaced with into R- (+) -1- phenyl ethylamine, other reaction conditions and embodiment
19 the step of (1), is identical, obtains white-yellowish solid, yield: 71.2%.
(2) preparation of (R)-N- [1- (4- aminophenyl) ethyl] acetamide
Step (2) N- in embodiment 19 [1- (4- nitrobenzophenone) ethyl] acetamide is replaced with into (R)-N- [1- (4- nitro
Phenyl) ethyl] acetamide, other reaction conditions are identical as (2) the step of embodiment 19, yellow oil is obtained, yield:
81.0%.
(3) preparation of (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline
Step (3) N- in embodiment 19 [1- (4- aminophenyl) ethyl] acetamide is replaced with into (R)-N- [1- (4- amino
Phenyl) ethyl] acetamide, other reaction conditions are identical as (3) the step of embodiment 19, faint yellow solid is obtained, yield:
75.0%.
(4) preparation of (R) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
By step (4) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinoline
Oxazoline replaces with (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline, other reactions
Condition is identical as (4) the step of embodiment 19, obtains white solid, yield: 82.8%.
(5) system of (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
It is standby
By step (5) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
Replace with (R) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and reality
The step of applying example 19 (5) is identical, obtains yellow solid, yield: 73.2%.
(6) (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) third oxygen
Base) quinazoline preparation
By step (6) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- chlorine
Base) quinazoline replaces with (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline azoles
Quinoline, other reaction conditions are identical as (6) the step of embodiment 19, obtain faint yellow solid, yield: 60.2%.Mp 122.1~
125.6℃。
Embodiment 26
(R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base) propoxyl group)
The preparation of quinazoline
By 4- in embodiment 20 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline azoles
Quinoline replaces with (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline, other are anti-
It answers condition and step identical as embodiment 20, obtains faint yellow solid, yield: 52.5%.124.6~125.7 DEG C of mp.
Embodiment 27
(R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dimethylamino) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 21 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(R) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and step and reality
It is identical to apply example 21, obtains light yellow oil, yield: 60.8%.
Embodiment 28
(R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 22 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(R) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and step and reality
It is identical to apply example 22, obtains pale solid, yield: 75.6%.176.3~178.1 DEG C of mp.
Embodiment 29
(R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 23 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(R) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and step and reality
It is identical to apply example 23, obtains faint yellow solid, yield: 76.0%.155.4~157.9 DEG C of mp.
Embodiment 30
(R) -4- [4- (1- amino-ethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
Preparation
By 4- in embodiment 24 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dibutyl amino)
Base) quinazoline replaces with (R) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- (dibutyl amino)
Base) quinazoline, other reaction conditions and step are identical as embodiment 24, obtain faint yellow solid, yield: 72.8%.mp 127.4
~130.6 DEG C.
Embodiment 31
(S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) propoxyl group)
The preparation of quinazoline
(S) preparation of-N- [1- (4- nitrobenzophenone) ethyl] acetamide
(1) (1) 1- phenyl ethylamine in embodiment 19 is replaced with into S- (-) -1- phenyl ethylamine, other reaction conditions and embodiment 19
The step of (1) it is identical, obtain white-yellowish solid, yield: 73.1%.
(2) preparation of (S)-N- [1- (4- aminophenyl) ethyl] acetamide
Step (2) N- in embodiment 19 [1- (4- nitrobenzophenone) ethyl] acetamide is replaced with into (S)-N- [1- (4- nitro
Phenyl) ethyl] acetamide, other reaction conditions are identical as (2) the step of embodiment 19, yellow oil is obtained, yield:
79.2%.
(3) preparation of (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline
Step (3) N- in embodiment 19 [1- (4- aminophenyl) ethyl] acetamide is replaced with into (S)-N- [1- (4- amino
Phenyl) ethyl] acetamide, other reaction conditions are identical as (3) the step of embodiment 19, obtain faint yellow solid, yield: 70.8%
(4) preparation of (S) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
By step (4) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinoline
Oxazoline replaces with (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- acetoxyl group quinazoline, other reactions
Condition is identical as (4) the step of embodiment 19, obtains white solid, yield: 78.0%.
(5) system of (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline
It is standby
By step (5) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride
Replace with (S) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and reality
The step of applying example 19 (5) is identical, obtains yellow solid, yield: 74.0%.
(6) (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- hexahydro piperidyl) third oxygen
Base) quinazoline preparation
By step (6) 4- in embodiment 19 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- chlorine
Base) quinazoline replaces with (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline azoles
Quinoline, other reaction conditions are identical as (6) the step of embodiment 19, obtain faint yellow solid, yield: 57.0%.Mp 121.4~
123.8℃。
Embodiment 32
(S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- nafoxidine base) propoxyl group)
The preparation of quinazoline
By 4- in embodiment 20 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinoline azoles
Quinoline replaces with (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- chloropropanol oxygen radical) quinazoline, other are anti-
It answers condition and step identical as embodiment 20, obtains faint yellow solid, yield: 56.3%.125.7~127.2 DEG C of mp.
Embodiment 33
(S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dimethylamino) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 21 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(S) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, step is identical as embodiment 21, obtains
Faint yellow solid, yield: 67.6%.Mp146.3~149.6 DEG C.
Embodiment 34
(S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (1- morpholinyl) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 22 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(S) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and step and reality
It is identical to apply example 22, obtains faint yellow solid, yield: 73.2%.189.3~192.4 DEG C of mp.
Embodiment 35
(S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinoline azoles
The preparation of quinoline
4- in embodiment 23 [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride is replaced with
(S) -4- [4- (1- acetamidoethyl) phenylamino] -6- hydroxyl -7- methoxyquinazoline hydrochloride, other reaction conditions and step and reality
It is identical to apply example 23, obtains faint yellow solid, yield: 77.0%.158.4~160.9 DEG C of mp.
Embodiment 36
(S) -4- [4- (1- amino-ethyl) phenylamino] -7- methoxyl group -6- (3- (dibutyl amino) propoxyl group) quinazoline
Preparation
By 4- in embodiment 24 [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (the third oxygen of 3- (dibutyl amino)
Base) quinazoline replaces with (S) -4- [4- (1- acetamidoethyl) phenylamino] -7- methoxyl group -6- (third oxygen of 3- (dibutyl amino)
Base) quinazoline, other reaction conditions and step are identical as embodiment 24, obtain faint yellow solid, yield: 76.5%.mp 127.8
~129.5 DEG C.
Above-mentioned target compound is synthesized using nuclear magnetic resonance hydrogen spectruming determining structure or high resolution mass spectrum measurement structure, structure
As shown in table 1.
The structural formula and its structure determination result of the compound of each embodiment of table 1 synthesis
The test of Primary Anti-Tumor biological evaluation
For the anti-tumor biological for further verifying above-described embodiment, this test choose embodiment 5,6,11,12,17,
18, target compound prepared by 23,24,29,30,35,36, using commercially available Gefitinib (Gifitinib) and OTS514 as
Comparison carries out pharmacological evaluation using MTT detection method, wherein it is as shown in table 2 to test cell strain and culture medium used.
Table 2 tests cell strain and culture medium used
Cell line | Cell type | Culture medium |
A549 | Lung carcinoma cell | RPMI-1640+10%FBS |
MDA-MB-231 | Breast cancer cell | DMEM+10%FBS |
The specific operation method is as follows:
The cancer cell digestion kind (8 × 104/mL) in 96 orifice plates of logarithmic growth phase is set 37 DEG C of temperature, 5%CO2Item
Adhere-wall culture is stayed overnight in incubator under part, supernatant is abandoned, according to such as the following group: normal group: without any processing;
Solvent control group (if drug is soluble in culture medium without setting solvent control): DMSO is added in cell culture medium makes it
Concentration is 0.2%;Positive drug control group: OTS514, (0.5 μM of Gefitinib;1μM;5μM;10μM;25μM;50μM;100μM);
Administration group: drug is according to 0.5 μM of concentration gradient;1μM;5μM;10μM;25μM;50μM;100 μM (each drug is dense
Degree sets 6 multiple holes), 100 μ L are administered, are placed in 37 DEG C, 5%CO2In incubator;After cell culture 48h/72h, inhales and abandon former culture
Base, every hole are added after MTT (0.5mgmL-1) 100 μ L culture medium is placed in incubator and continues to cultivate 4h, purple crystal occur,
MTT solution is discarded, every hole is added 150 μ L DMSO, is placed in shaking table 10min;Absorbance is measured under 490nm wavelength with microplate reader
(OD value) calculates survival rate.
It is handled using statistics software SPSS Statistics21, calculates IC50 with it, testing result is as shown in table 3.
3 antitumor activity of compound test structure of table
As can be seen from Table 3, for A549 cell line, prepared by the embodiment of the present invention 6,11,12,18,24,29,30 and 36
Target compound activity be higher than positive control Gefitinib;The bioactivity of embodiment 5,17,23 and 35 with
Gefitinib is suitable, shows that the target compound of synthesis can become anti-tumor drug candidate.Embodiment 6,12,24,30 and 36
Bioactivity it is suitable with OTS514, show that novel chiral PBK/TOPK inhibitor candidate can be become, it is more preferable to find activity
Compound provide may.To MDA-MB-231 cell line, the embodiment of the present invention 5,6,11,12,17,18,23,24,29,30,
35,36 bioactivity are above positive control Gefitinib.Therefore, target compound prepared in the above embodiments can be used
In preparing anticancer drug, it to be especially used for the preparation of anti-lung-cancer medicament or anti-breast cancer medicines.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Each technical characteristic of embodiment described above can carry out arbitrarily
Combination, for simplicity of description, it is not all possible to each technical characteristic in above-described embodiment combination be all described, so
And as long as there is no contradiction in the combination of these technical features, it all should be considered as described in this specification.
Claims (10)
1. quinazoline derivant, which is characterized in that have the following structure formula:
In formula ,-R1Selected from 2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, 2- amino -1- Methylethyl, 1- acetamidoethyl, 1- amino
Ethyl, (R) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (S) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (R) -2- amino -1- methyl second
Base, (S) -2- amino -1- Methylethyl, (R) -1- acetamidoethyl, (S) -1- acetamidoethyl, (R) -1- amino second
One of base, (S) -1- amino-ethyl;-R2Selected from hexahydro piperidines propyl, nafoxidine propyl, dimethylamine propyl, morpholine third
One of base, dibutyl amine propyl.
2. quinazoline derivant according to claim 1, which is characterized in that the quinazoline derivant is tied selected from following
One of structure formula:
3. a kind of preparation method of the described in any item quinazoline derivants of claim 1-2, which is characterized in that including following step
It is rapid:
1) compound A1 and sodium hydroxide solution are subjected to neutralization reaction, obtain compound A2, the structural formula of the compound A1 isThe structural formula of the compound A2 is-R3Selected from 2- amino -1- Methylethyl, (R) -2- ammonia
Base -1- Methylethyl, (S) -2- amino -1- Methylethyl, 1- amino-ethyl, (R) -1- amino-ethyl, (S) -1- amino-ethyl
One of;Later in methylene chloride by compound A2 dissolution, it is cooled to -5~0 DEG C, aceticanhydride solution is added dropwise and carries out acyl
Change reaction, obtains compound A-13, the structural formula of the compound A-13 is-R1Selected from 2- acetylaminohydroxyphenylarsonic acid 1- methyl second
Base, 2- amino -1- Methylethyl, 1- acetamidoethyl, 1- amino-ethyl, (R) -2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (S) -
2- acetylaminohydroxyphenylarsonic acid 1- Methylethyl, (R) -2- amino -1- Methylethyl, (S) -2- amino -1- Methylethyl, (R) -1- acetyl
One of amino-ethyl, (S) -1- acetamidoethyl, (R) -1- amino-ethyl, (S) -1- amino-ethyl;
2) it in methylene chloride by compound A-13 dissolution, is cooled to -5~0 DEG C, mixed acid solution is slowly added dropwise and nitrify instead
It answers, obtains compound A4, the structural formula of the compound A4 is
3) nitro on the compound A4 phenyl ring is reduced into amino, obtains compound A-45, the structural formula of the compound A-45
For
4) substitution reaction is occurred into for compound B3 and the compound A-45 and obtains compound A6, the structural formula of the compound A6 isThe structural formula of the compound B3 is
5) hydrolysis is occurred into for the compound A6 and ammonium hydroxide, obtains compound A7, the structural formula of the compound A7 is
6) substitution reaction is occurred into for the compound A7 and compound M, obtains compound A-28, wherein the compound M be containing-
R2Group ,-R2One in hexahydro piperidines propyl, nafoxidine propyl, dimethylamine propyl, morpholine propyl, dibutyl amine propyl
Kind, the structural formula of the compound A-28 is
4. preparation method according to claim 3, which is characterized in that further include the compound B3 before step 4)
Preparation: acylation reaction is occurred into for compound B-11 and aceticanhydride, obtains compound B2, the structural formula of the compound B-11 isThe structural formula of the compound B2 isBy the compound B2 and protochloride
Halogenation occurs for sulfone, obtains the compound B3.
5. preparation method according to claim 3, which is characterized in that compound A2 described in step 1) and the aceticanhydride are molten
The dosage molar ratio of aceticanhydride in liquid is 1:1.2~1.5, and the reaction time is 8~10h.
6. the preparation method according to claim 4, which is characterized in that acylation reaction occurs for the compound B-11 and aceticanhydride
Reaction temperature is 95~100 DEG C, and the time is 5~8h.
7. preparation method according to claim 3, which is characterized in that compound A-45 described in step 4) and the compound
The dosage molar ratio that substitution reaction occurs for B3 is 1:0.8~0.9, and reaction temperature is 90 DEG C~100 DEG C, and the reaction time is 4~6h.
8. the described in any item quinazoline derivants of claim 1-2 are preparing the application in PBK/TOPK inhibitor.
9. the described in any item quinazoline derivants of claim 1-2 are preparing the application in anticancer drug.
10. application according to claim 9, which is characterized in that the anticancer drug includes anti-lung-cancer medicament and anti-mammary gland
Cancer drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910249262.4A CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910249262.4A CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109942499A true CN109942499A (en) | 2019-06-28 |
CN109942499B CN109942499B (en) | 2022-03-22 |
Family
ID=67013192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910249262.4A Active CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109942499B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113845485A (en) * | 2021-10-22 | 2021-12-28 | 湖南中医药大学 | Amino acid derivative and preparation method and application thereof |
CN114907261A (en) * | 2022-04-01 | 2022-08-16 | 湖南中医药大学 | 2-phenylamino quinoline derivative and preparation method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102775356A (en) * | 2011-05-13 | 2012-11-14 | 江苏恒谊药业有限公司 | 4-aminoquinazoline derivative and application thereof |
CN103254142A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-subtituted amino acetylamino)phenylamino] quinazoline derivative as well as preparation method and application thereof |
CN106045980A (en) * | 2016-06-03 | 2016-10-26 | 江苏开放大学 | Quinazoline derivative and preparation method thereof |
-
2019
- 2019-03-29 CN CN201910249262.4A patent/CN109942499B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102775356A (en) * | 2011-05-13 | 2012-11-14 | 江苏恒谊药业有限公司 | 4-aminoquinazoline derivative and application thereof |
CN103254142A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-subtituted amino acetylamino)phenylamino] quinazoline derivative as well as preparation method and application thereof |
CN106045980A (en) * | 2016-06-03 | 2016-10-26 | 江苏开放大学 | Quinazoline derivative and preparation method thereof |
Non-Patent Citations (5)
Title |
---|
崔智勇 等: "喹唑啉类化合物的合成及抗肿瘤活性", 《北京医科大学学报》 * |
李付刚等: "喹唑啉类抗癌药物的合成研究进展", 《精细与专用化学品》 * |
邵薇等: "新型喹唑啉类衍生物的合成与抗肿瘤活性的研究", 《华西药学杂志》 * |
黄晴菲等: "新型氨基喹唑啉化合物的合成及其抗肿瘤活性", 《合成化学》 * |
黄珍等: "新型TOPK抑制剂的设计、合成及抗肿瘤活性研究", 《湖南中医药大学学报》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113845485A (en) * | 2021-10-22 | 2021-12-28 | 湖南中医药大学 | Amino acid derivative and preparation method and application thereof |
CN113845485B (en) * | 2021-10-22 | 2023-03-14 | 湖南中医药大学 | Amino acid derivative and preparation method and application thereof |
CN114907261A (en) * | 2022-04-01 | 2022-08-16 | 湖南中医药大学 | 2-phenylamino quinoline derivative and preparation method and application thereof |
CN114907261B (en) * | 2022-04-01 | 2023-10-27 | 湖南中医药大学 | 2-phenylaminoquinoline derivative, preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN109942499B (en) | 2022-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
WO2018024208A1 (en) | Ido1 inhibitor and preparation method and application thereof | |
CN111819177B (en) | Crystal form and salt form of pyridino-imidazole compound and preparation method thereof | |
CN110713500B (en) | Palladium complex using 2-benzoylpyridine thiosemicarbazone and synthetic method thereof | |
CN109942499A (en) | Quinazoline derivant and its preparation method and application | |
CN106220641A (en) | Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application | |
CN111646941A (en) | Sulfonamide derivative and preparation method and application thereof | |
WO2014173029A1 (en) | Nitrogen mustard derivatives, method of preparing same, and tumor treatment application | |
CN112047880B (en) | Azaflavone derivatives and application thereof as antitumor drugs | |
CN101948467A (en) | Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines | |
CN108997319B (en) | Thioimidazolidone derivative and synthesis method and application thereof | |
CN107827934B (en) | Tetravalent platinum complex with anticancer activity, preparation method and application | |
CN110143995A (en) | Azacyclo- replaces 18 β-Enoxolone derivative and its preparation and application | |
CN110526955B (en) | 18 beta-glycyrrhetinic acid compound containing hydroxamic acid structural fragment and application thereof | |
CN107163028A (en) | A kind of benzamides Hedgehog inhibitor and its preparation method and application | |
CN109053841B (en) | 6-disulfur substituted-2' -deoxyguanosine compound and preparation method and application thereof | |
CN104961725B (en) | 4-alpha, beta-unsaturated carboxamidoquinoline compounds and preparation and application | |
CN110698512B (en) | Tin complex with 2-acetylpyridine thiosemicarbazone as ligand and synthesis method thereof | |
CN107200731A (en) | A kind of Pyridione derivatives containing thiazole ring and its preparation method and application | |
CN104803878B (en) | A kind of O benzoyls (4 trifluoromethyl) salicylamide compound and its application | |
CN110981771A (en) | Preparation method and application of impurity E of suplatast tosilate process | |
CN108640965A (en) | 2- replaces -18 β-Enoxolone derivatives and its application | |
CN109160902B (en) | Asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof | |
CN115073547B (en) | Steroid carboline derivative, preparation method and application thereof, and anti-tumor pharmaceutical composition | |
CN111777626B (en) | Venetian-dihydroartemisinin split compound and preparation and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |