CN105859638B - A kind of ring succinamide compound with anti-tumor activity and its preparation method and application - Google Patents
A kind of ring succinamide compound with anti-tumor activity and its preparation method and application Download PDFInfo
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- CN105859638B CN105859638B CN201610280785.1A CN201610280785A CN105859638B CN 105859638 B CN105859638 B CN 105859638B CN 201610280785 A CN201610280785 A CN 201610280785A CN 105859638 B CN105859638 B CN 105859638B
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- ONDRCTKZMCDKMQ-UHFFFAOYSA-N CCCCC(C(NC(C=C1)C#CC=C1c1cc(N=CNC(C2)=O)c2cc1)=O)C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O Chemical compound CCCCC(C(NC(C=C1)C#CC=C1c1cc(N=CNC(C2)=O)c2cc1)=O)C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O ONDRCTKZMCDKMQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
Abstract
The present invention provides a kind of ring succinamide compounds with anti-tumor activity and its preparation method and application, and the structural formula of the compound isWherein R1、R2For hydrogen, alkane group or halogen group.The compound has good inhibitory activity to 2 kinases of VEGFR, can be by the activity of inhibition 2 kinases of VEGFR, and the signal path for blocking it to induce inhibits hyperplasia and the migration of tumour cell, so as to the preparation applied to antitumor drug.And the preparation method of the compound is easy to get with raw material, reaction condition is mild, and reaction process is easy to operate, the cheap advantage of agents useful for same.
Description
Technical field
The invention belongs to biomedicine technical fields, are related to a kind of antitumor compound, more particularly to a kind of with anti-
Ring succinamide compound of tumor promotion and its preparation method and application.
Background technology
The malignant tumour public health problem one of larger as the whole world, greatly endangers the health of the mankind, and will become
The first killer of the new century mankind.Malignant tumour has no longer been the serious disease of advanced industrial country, and developing country faces
The Disease Spectrum of bigger.Chemotherapy had huge as one of the important means for the treatment of tumour at nearly 30 years
Big development and progress has obtained large quantities of clinical antitumor agents with different role mechanism.But antineoplastic is also deposited
In many adverse reactions, such as alopecia, vomiting generates bone marrow suppression, quickly generates drug resistance etc., these result in chemical drugs
Object is unable to reach expected therapeutic effect.Therefore new antitumor drug research and development be current pharmaceutical field hot spot and
One of difficulties.
Invention content
The purpose of the present invention is to provide a kind of ring succinamide compounds with anti-tumor activity and preparation method thereof
And application, the compound embody good antitumor activity in vitro, can be applied to the preparation of antitumor drug.
In order to achieve the above objectives, the present invention uses following technical scheme：
A kind of ring succinamide compound with anti-tumor activity, chemical structural formula are as follows：
Wherein, R1、R2For hydrogen, alkane group or halogen group.
The halogen group is fluorine atom, chlorine atom, bromine atom or trifluoromethyl.
The alkane group is methyl or ethyl.
The preparation method of the ring succinamide compound with anti-tumor activity, includes the following steps：
1) 2- amino -4- bromobenzoic acids prepare -4 (3H) -one of 7- bromines quinazoline with formamide by ring-closure reaction；
2) under the catalytic action of tetrakis triphenylphosphine palladium, -4 (3H) -one of 7- bromines quinazoline and p-aminophenyl boric acid hydrochloric acid
Biphenol compound is obtained by the reaction by Suzuki in salt；
3) 1,1 cyclobutyl dioctyl phthalate occur acylation reaction under the conditions of thionyl chloride with monosubstituted or disubstituted aniline and obtain
To monoacylated fourth formic acid；
4) biphenol compound, which is generated with monoacylated fourth formic acid under the condensation of HATU condensing agents, has antitumor work
The ring succinamide compound of property.
The concrete operations of the step 1) are：2- amino -4- bromobenzoic acids are dissolved in formamide, under nitrogen protection into
Reaction solution is added in ice water, is extracted with ethyl acetate after reaction by row reaction, the organic phase of extraction is washed, it is dry after
Decompression boils off solvent, obtains rufous residue, with chromatography post separation rufous residue, obtains red brown solid 7- bromine quinoline azoles
Quinoline -4 (3H)-ketone.
The concrete operations of the step 2) are：By 7- bromines quinazoline -4 (3H) -one, p-aminophenyl boric acid hydrochloride, anhydrous
Potassium carbonate and tetrakis triphenylphosphine palladium are dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, are reacted under nitrogen protection, reaction
After be cooled to room temperature, be extracted with ethyl acetate, the organic phase of extraction is washed, it is dry after decompression boil off solvent, obtain crude product,
With chromatography post separation crude product, biphenol compound is obtained.
The concrete operations of the step 3) are：Under nitrogen protection, anhydrous triethylamine is added drop-wise to 1,1 cyclobutyl dioctyl phthalate
Anhydrous tetrahydrofuran solution in, be stirred to react under condition of ice bath, then thereto be added dropwise thionyl chloride anhydrous tetrahydro furan
Solution is stirred to react, then the anhydrous tetrahydrofuran solution of monosubstituted or disubstituted aniline is added dropwise thereto, is stirred to react, instead
After answering, decompression after reaction solution washing, drying is boiled off into solvent, crude product is obtained, with chromatography post separation crude product, obtains monoacylated
Fourth formic acid.
The concrete operations of the step 4) are：Under condition of ice bath, biphenol compound and monoacylated fourth formic acid are added
Into anhydrous tetrahydro furan, HATU is added, is stirred to react, the tetrahydrofuran solution of anhydrous triethylamine is then added thereto,
Remove ice bath, react at room temperature, after reaction, be extracted with ethyl acetate, the organic phase of extraction is washed, it is dry after depressurize and steam
Solvent is removed, crude product is obtained, with chromatography post separation crude product, obtains ring succinamide compound with anti-tumor activity.
The ring succinamide compound with anti-tumor activity inhibits the drug of VEGFR-2 kinase activities preparing
In application.
The ring succinamide compound with anti-tumor activity is being prepared using VEGFR-2 kinases as the anti-swollen of target spot
Application in tumor medicine.
Compared with prior art, the invention has the advantages that：
Ring succinamide compound with anti-tumor activity provided by the invention is that a kind of novel have antitumor work
The compound of property, has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antitumor drug.Specifically, this hair
The ring succinamide compound with anti-tumor activity of bright offer, can inhibit the activity of VEGFR-2 kinases.And angiogenesis
Generation, development and migration with tumour have substantial connection, inhibit the formation of new vessels that can effectively inhibit the life of tumour
Long and migration, many growth factor regulation and control new vessels generate, and wherein VEGFR-2 is known strongest positive regulatory factor.Cause
This ring succinamide compound with anti-tumor activity provided by the invention is blocked by the activity of inhibition VEGFR-2 kinases
Its signal path induced inhibits hyperplasia and the migration of tumour cell, so as to the preparation applied to antitumor drug, especially
Using VEGFR-2 kinases as the antitumor drug of target spot and the drug of inhibition VEGFR-2 kinase activities.
The preparation method of ring succinamide compound with anti-tumor activity provided by the invention, passes through 2- amino -4-
Bromobenzoic acid obtains 7- bromines quinazoline -4 (3H) -one with formamide, then connection is obtained by the reaction with p-aminophenyl boric acid hydrochloride
Benzene compound, and monoacylated fourth formic acid is obtained by 1,1 cyclobutyl dioctyl phthalate and monosubstituted or disubstituted aniline reaction, it will
Substituent group in aniline is introduced on monoacylated fourth formic acid, and then biphenol compound is condensed with monoacylated fourth formic acid again
Reaction is to get to ring succinamide compound with anti-tumor activity, and this method is easy to get with raw material, and reaction condition is mild,
Reaction process is easy to operate, the cheap advantage of agents useful for same.
Description of the drawings
Fig. 1 is the synthetic route chart of ring succinamide compound with anti-tumor activity provided by the invention；
Wherein, compound 1 is 2- amino -4- bromobenzoic acids, and compound 2 is 7- bromines quinazoline -4 (3H) -one, compound 3
For p-aminophenyl boric acid hydrochloride, compound 4 is biphenol compound；It is 1,1 cyclobutyl dioctyl phthalate that compound, which is 5, and compound 6 is
Monosubstituted or disubstituted aniline, compound 7 are monoacylated fourth formic acid, and compound 8 is ring fourth two with anti-tumor activity
Amide compound.
Marked in figure be specially：
a.HCONH2,MW,150℃；b.Pd(PPh3)4,K2CO3,H2O,dioxane,100℃；c.SOCl2,Et3N,DCM,0
℃； d.HATU,Et3N,THF,rt.
Specific implementation mode
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, and described is to the present invention
It explains rather than limits.
The present invention provides a kind of ring succinamide compound with anti-tumor activity, which exists
There is antitumor activity in vitro, can be applied to the preparation of antitumor drug.
Contain quinazoline ketone group in the structural formula of ring succinamide compound with anti-tumor activity provided by the invention
Group, chemical structural formula are specific as follows：
Wherein, R1、R2For hydrogen, alkane group or halogen group.The halogen group is fluorine atom, chlorine atom, bromine atom
Or trifluoromethyl.
Carry out the tool that the present invention will be described in detail provides with reference to synthetic route shown in Fig. 1 and specific synthetic example
There are preparation and the method for screening active ingredients of the drug candidate ring succinamide compound of antitumor activity.
Embodiment 1
In the structural formula of the ring succinamide compound with anti-tumor activity, R1For hydrogen, R2For F, pass through following steps
It prepares (referring to Fig. 1)：
1) 2- amino -4- bromobenzoic acids (compound 1) prepare 7- bromines quinazoline -4 (3H)-with formamide by ring-closure reaction
Ketone (compound 2)
5.0g (23.14mmol) 2- amino -4- bromobenzoic acids are dissolved in 80ml (2.01mmol) formamide, nitrogen protection
Under 150 DEG C, power be 300W microwave condition under react 1.45h, after reaction, by reaction solution be added ice water in, use second
Acetoacetic ester extracts 3-4 time, and the organic phase of extraction is successively with saturated sodium bicarbonate solution and saturated common salt water washing, then with anhydrous sulphur
Sour sodium drying, is then spin-dried for, obtains rufous residue, with chromatography post separation rufous residue, obtains red brown solid 7-
Bromine quinazoline -4 (3H) -one 1.89g, yield 36.3%.
2) by 7- bromines quinazoline -4 (3H) -one (compound 2) and p-aminophenyl under tetrakis triphenylphosphine palladium catalysis reaction
4 ((3H) -7- quinazoline-4-ones) aniline (compound 4) are obtained by the reaction by Suzuki in boric acid hydrochloride (compound 3)；
By -4 (3H) -one of 0.87g (3.87mmol) 7- bromines quinazoline, 0.61g (3.52mmol) p-aminophenyl boric acid hydrochloric acid
Salt, 1.46g (10.56mmol) Anhydrous potassium carbonates and 0.4g (0.35mmol) tetrakis triphenylphosphine palladium are dissolved in 90mL 1,4- dioxies
In the mixed solution of six rings and 30mL water, under nitrogen protection overnight in 100 DEG C of reactions, it is cooled to room temperature, uses after reaction
Ethyl acetate extracts, the organic phase of extraction is washed, it is dry after decompression boil off solvent, obtain crude product, with chromatography post separation crude product, obtain
To yellow solid 4 ((3H) -7- quinazoline-4-ones) aniline 0.72g, yield 85.7%.
3) 1,1 cyclobutyl dioctyl phthalate (compound 5) are acylated with m-fluoroaniline (compound 6) under the conditions of thionyl chloride
1- ((3- fluorophenyls) carbamyl) ring fourth formic acid (compound 7) is obtained by the reaction；
Under nitrogen protection, 1ml (6.94mmol) anhydrous triethylamine is slowly dropped to 1,1 cyclobutyl of 1g (6.94mmol)
In the anhydrous tetrahydrofuran solution 20ml of dioctyl phthalate, it is stirred to react 30min under condition of ice bath, then continues to be added dropwise thereto slow
The anhydrous tetrahydrofuran solution 5ml of 0.5ml (6.94mmol) thionyl chloride, is stirred to react 2 hours, then be slowly added dropwise thereto
The anhydrous tetrahydrofuran solution 20ml of 0.77g (6.94mmol) m-fluoroaniline is stirred to react 2 hours, after reaction, will be anti-
Decompression boils off solvent after answering liquid washing, drying, obtains crude product, with chromatography post separation crude product, obtains white solid 1- ((3- fluorophenyls)
Carbamyl) ring fourth formic acid 0.51g, yield 30.9%.
4) 4 ((3H) -7- quinazoline-4-ones) aniline (compound 4) and 1- ((3- fluorophenyls) carbamyl) ring fourth formic acid
(compound 7) generates target compound (compound 8) under the condensation of HATU condensing agents.
Under condition of ice bath, by ((the 3H) -7- quinazoline-4-ones) aniline of 0.13g (0.53mmol) 4 and 0.19g
(0.80mmol) 1- ((3- fluorophenyls) carbamyl) ring fourth formic acid is added in 15ml anhydrous tetrahydro furans, adds 0.36g
(0.95mmol) HATU, be stirred to react be slowly added to after 30min 0.07ml (0.53mmol) anhydrous triethylamine tetrahydrofuran it is molten
Liquid 3ml removes ice bath, and reaction at room temperature overnight, after reaction, reaction solution is extracted with ethyl acetate, the organic phase of extraction
Decompression boils off solvent after washed, dry, obtains crude product, with chromatography post separation crude product, obtains target compound 0.18g, yield
75.0%.
The structure of gained target compound is as follows：
Physicochemical property：mp:>300℃.
Hydrogen composes nuclear magnetic resonance data：1H NMR(400MHz,DMSO)δ9.87(s,1H),9.83(s,1H),8.16(d,J
=8.3Hz, 1H), 8.14 (s, 1H), 7.91 (d, J=1.3Hz, 1H), 7.87 (s, 1H), 7.84 (s, 2H), 7.80 (d, J=
8.8Hz, 2H), 7.73-7.66 (m, 1H), 7.48 (d, J=8.4Hz, 1H), 7.34 (m, J=15.2,8.1Hz, 1H), 6.90
(td, J=8.5,2.4Hz, 1H), 2.69 (t, J=7.9Hz, 4H), 1.92-1.81 (m, 2H)
Carbon composes nuclear magnetic resonance data：13C NMR(101MHz,DMSO)δ170.69,170.42,161.26,161.03,
149.67, 146.35,145.78,141.31,140.01,133.97,130.60,127.87,127.03,125.44,
124.43,121.59,120.90, 116.17,110.56,110.35,107.32,107.05,56.99,29.77,15.83.
Embodiment 2
In the structural formula of the ring succinamide compound with anti-tumor activity, R1、R2It is trifluoromethyl.
Step 1)~step 3) is identical as step 1)~step 3) in embodiment 1, i.e., by initial compounds 2- amino -4-
Bromobenzoic acid (compound 1) prepares -4 (3H) -one (compound 2) of 7- bromines quinazoline, 7- bromine quinolines with formamide by ring-closure reaction
4 ((3H)-are obtained by the reaction by Suzuki with p-aminophenyl boric acid hydrochloride (compound 3) in oxazoline -4 (3H) -one (compound 2)
7- quinazoline-4-ones) aniline (compound 4), 1,1 cyclobutyl dioctyl phthalate (compound 5) and 3,5-, bis- 5-trifluoromethylaniline (chemical combination
Object 6) generation acylation reaction obtains 1- ((bis- trifluoromethyls of 3,5-) carbamyl) ring fourth formic acid under the conditions of thionyl chloride
(compound 7).
4) 4 ((3H) -7- quinazoline-4-ones) aniline (compound 4) and 1- ((bis- trifluoromethyls of 3,5-) amino first
Acyl) ring fourth formic acid (compound 7) generation target compound (compound 8), specific operating procedure under the condensation of HATU condensing agents
For：
Under condition of ice bath, by ((the 3H) -7- quinazoline-4-ones) aniline of 0.45g (1.88mmol) 4 and 1.00g
(2.81mmol) 1- ((3,5- bis- trifluoromethyl) carbamyl) ring fourth formic acid is added in 30ml anhydrous tetrahydro furans,
2.14g (5.64mmol) HATU is added, 0.78ml (5.64mmol) anhydrous triethylamine is slowly added to after being stirred to react 30min
Tetrahydrofuran solution 20ml, remove ice bath, at room temperature reaction overnight, after reaction, reaction solution is extracted with ethyl acetate,
The organic phase of extraction is washed, it is dry after decompression boil off solvent, obtain crude product, with chromatography post separation crude product, obtain target compound
0.23g, yield 21.3%.
The structure of gained target compound is as follows：
Physicochemical property：mp:>300℃.
Hydrogen composes nuclear magnetic resonance data：1H NMR(400MHz,DMSO)δ12.30(s,1H),11.03(s,1H),10.38
(s, 1H), 8.57 (s, 2H), 8.16 (d, J=8.3Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.92 (d, J=
12.1Hz, 2H), 7.82 (d, J=12.8Hz, 2H), 7.77 (d, J=9.4Hz, 2H), 2.74 (t, J=7.5Hz, 4H),
1.94–1.78(m,2H).
Carbon composes nuclear magnetic resonance data：1H NMR(400MHz,DMSO)δ12.30(s,1H),11.03(s,1H),10.38
(s, 1H), 8.57 (s, 2H), 8.16 (d, J=8.3Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.92 (d, J=
12.1Hz, 2H), 7.82 (d, J=12.8Hz, 2H), 7.77 (d, J=9.4Hz, 2H), 2.74 (t, J=7.5Hz, 4H),
1.94–1.78(m,2H).
Embodiment 3
In the structural formula of the ring succinamide compound with anti-tumor activity, R1For chlorine, R2For CH3。
Step 1)~step 3) is identical as step 1)~step 3) in embodiment 1, i.e., by initial compounds 2- amino -4-
Bromobenzoic acid (compound 1) prepares -4 (3H) -one (compound 2) of 7- bromines quinazoline, 7- bromine quinolines with formamide by ring-closure reaction
4 ((3H)-are obtained by the reaction by Suzuki with p-aminophenyl boric acid hydrochloride (compound 3) in oxazoline -4 (3H) -one (compound 2)
7- quinazoline-4-ones) aniline (compound 4), 1,1 cyclobutyl dioctyl phthalate (compound 5) and the chloro- 4- methylanilines (compounds of 3-
6) acylation reaction occurs under the conditions of thionyl chloride and obtains 1- ((the chloro- 4- aminomethyl phenyls of 3-) carbamyl) ring fourth formic acid (chemical combination
Object 7).
4) 4 ((3H) -7- quinazoline-4-ones) aniline (compound 4) and 1- ((the chloro- 4- aminomethyl phenyls of 3-) carbamyl) ring
Fourth formic acid (compound 7) generates target compound (compound 8) under the condensation of HATU condensing agents, and specific operating procedure is：
Under condition of ice bath, by ((the 3H) -7- quinazoline-4-ones) aniline of 0.59g (2.49mmol) 4 and 1.00g
(3.74mmol) 1- ((the chloro- 4- aminomethyl phenyls of 3-) carbamyl) ring fourth formic acid is added in 30ml anhydrous tetrahydro furans, then is added
Enter 2.84g (7.47mmol) HATU, the four of 01.00ml (7.47mmol) anhydrous triethylamine is slowly added to after being stirred to react 30min
Hydrogen tetrahydrofuran solution 20ml, removes ice bath, and overnight, after reaction, reaction solution is extracted with ethyl acetate for reaction at room temperature, is extracted
Organic phase it is washed, it is dry after decompression boil off solvent, obtain crude product, with chromatography post separation crude product, obtain target compound
0.25g, yield 20.7%.
The structure of gained target compound is as follows：
Physicochemical property：mp:>300℃.
Hydrogen composes nuclear magnetic resonance data：1H NMR(400MHz,DMSO)δ12.26(s,1H),9.83(s,1H),9.80(s,
1H), 8.16 (d, J=8.3Hz, 1H), 8.13 (s, 1H), 7.89 (d, J=9.6Hz, 2H), 7.86 (d, J=8.9Hz, 2H),
7.81 (s, 2H), 7.79 (s, 1H), 7.52 (d, J=7.9Hz, 1H), 7.27 (d, J=8.2Hz, 1H), 2.68 (t, J=
7.3Hz,4H),2.27(s,3H), 1.94–1.74(m,2H).
Carbon composes nuclear magnetic resonance data：13C NMR(101MHz,DMSO)δ170.54,170.46,161.02,149.80,
146.29, 145.77,140.03,138.62,133.95,133.27,131.45,130.62,127.86,127.01,
125.41,124.53,121.61, 120.88,120.50,119.12,56.90,29.78,19.40,15.82.
The suppression of VEGFR-2 kinases is carried out to ring succinamide compound with anti-tumor activity produced by the present invention below
Screening active ingredients processed.
With HTRF KinEASE kit measurements ring succinamide compound with anti-tumor activity produced by the present invention
To the inhibitory activity of VEGFR-2：Inhibitory activity of the detection ring succinamide compound to VEGFR-2, behaviour are tested using Lance
Make method to illustrate to carry out according to kit.The substrate of 2 μ L kinases and 2 μ L are added in 384 orifice plates, VEGFR-2 is a concentration of
0.09ng/ μ L, concentration of substrate 180nM.Then the substrate polypeptide and 4 μ L untested compounds of various concentration is added, 2 μ L are added
ATP starts reaction, after reacting 30min at 37 DEG C, EDTA is added and terminates reaction.It is separately added into after reaction into reaction solution
Eu3+The antibody and streptavidin-XL665 of cryptate label, are incubated at room temperature 1h, using Perkin-
Elmer Victor 5 measure absorbance, kinase activity A665/A615 × 10 respectively under 665nm and 615nm wavelength4Table
Sign calculates inhibiting rate and IC of the ring succinamide compound with anti-tumor activity provided by the invention to VEGFR-250。
Inhibitory activity knot of the ring succinamide compound with anti-tumor activity provided by the invention to VEGFR-2 kinases
Fruit is as shown in table 1：
The VEGFR-2 inhibitory activity of 1 ring succinamide compound of table
As can be seen from Table 1, the ring succinamide compound with anti-tumor activity that prepared by the present invention swashs VEGFR-2
Enzyme has inhibitory activity, can be used for preparing the drug for inhibiting VEGFR-2 kinase activities and prepares using VEGFR-2 kinases as target spot
Antitumor drug.
To the preferable ring fourth of VEGFR-2 kinase inhibitory effects in above-mentioned ring succinamide compound with anti-tumor activity
The concrete structure of diamide compound is as shown in table 2.
The structural formula of 2 ring succinamide compound of table.
Claims (10)
1. a kind of ring succinamide compound with anti-tumor activity, which is characterized in that its chemical structural formula is as follows：
Wherein, R1、R2For hydrogen, alkane group or halogen group.
2. ring succinamide compound with anti-tumor activity as described in claim 1, which is characterized in that the halogen
Group is fluorine atom, chlorine atom or bromine atom.
3. ring succinamide compound with anti-tumor activity as described in claim 1, which is characterized in that the alkane
Group is methyl or ethyl.
4. the preparation method of the ring succinamide compound with anti-tumor activity described in any one of claim 1-3,
It is characterized by comprising the following steps：
1) 2- amino -4- bromobenzoic acids prepare -4 (3H) -one of 7- bromines quinazoline with formamide by ring-closure reaction；
2) under the catalytic action of tetrakis triphenylphosphine palladium, -4 (3H) -one of 7- bromines quinazoline is logical with p-aminophenyl boric acid hydrochloride
It crosses Suzuki and biphenol compound is obtained by the reaction；
3) 1,1- cyclobutyl dioctyl phthalate occurs acylation reaction under the conditions of thionyl chloride with monosubstituted or disubstituted aniline and obtains
Monoacylated 1,1- cyclobutyl dioctyl phthalate；
4) biphenol compound is generated under the condensation of HATU condensing agents with monoacylated 1,1- cyclobutyl dioctyl phthalate with anti-
The ring succinamide compound of tumor promotion.
5. wanting the preparation method of the ring succinamide compound with anti-tumor activity described in 4 according to right, it is characterised in that：
The concrete operations of the step 1) are：2- amino -4- bromobenzoic acids are dissolved in formamide, are reacted under nitrogen protection,
After reaction, reaction solution is added in ice water, is extracted with ethyl acetate, the organic phase of extraction is washed, it is dry after depressurize and steam
Solvent is removed, rufous residue is obtained, with chromatography post separation rufous residue, obtains red brown solid 7- bromines quinazoline -4
(3H) -one.
6. wanting the preparation method of the ring succinamide compound with anti-tumor activity described in 4 according to right, it is characterised in that：
The concrete operations of the step 2) are：By 7- bromines quinazoline -4 (3H) -one, p-aminophenyl boric acid hydrochloride, Anhydrous potassium carbonate and
Tetrakis triphenylphosphine palladium is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, is reacted under nitrogen protection, cold after reaction
But to room temperature, be extracted with ethyl acetate, the organic phase of extraction is washed, it is dry after decompression boil off solvent, obtain crude product, use chromatographic column
Crude product is detached, biphenol compound is obtained.
7. wanting the preparation method of the ring succinamide compound with anti-tumor activity described in 4 according to right, it is characterised in that：
The concrete operations of the step 3) are：Under nitrogen protection, anhydrous triethylamine is added drop-wise to the anhydrous of 1,1- cyclobutyl dioctyl phthalate
It in tetrahydrofuran solution, is stirred to react under condition of ice bath, the anhydrous tetrahydrofuran solution of thionyl chloride is then added dropwise thereto, stirs
Reaction is mixed, then the anhydrous tetrahydrofuran solution of monosubstituted or disubstituted aniline is added dropwise thereto, is stirred to react, reaction terminates
Afterwards, decompression after reaction solution washing, drying is boiled off into solvent, obtains crude product, with chromatography post separation crude product, obtain monoacylated 1,1- rings
Butyl dioctyl phthalate.
8. wanting the preparation method of the ring succinamide compound with anti-tumor activity described in 4 according to right, it is characterised in that：
The concrete operations of the step 4) are：Under condition of ice bath, biphenol compound and monoacylated 1,1- cyclobutyl dioctyl phthalate are added
Enter into anhydrous tetrahydro furan, add HATU, be stirred to react, the tetrahydrofuran that anhydrous triethylamine is then added thereto is molten
Liquid removes ice bath, reacts at room temperature, after reaction, is extracted with ethyl acetate, the organic phase of extraction is washed, it is dry after subtract
Pressure boils off solvent, obtains crude product, with chromatography post separation crude product, obtains ring succinamide compound with anti-tumor activity.
9. the ring succinamide compound with anti-tumor activity described in any one of claim 1-3 is preparing inhibition
Application in the drug of VEGFR-2 kinase activities.
10. ring succinamide compound with anti-tumor activity described in any one of claim 1-3 prepare with
VEGFR-2 kinases is the application in the antitumor drug of target spot.
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