CN105859638A - Cyclobutane-diamide compound with antitumor activity and preparation method and application thereof - Google Patents
Cyclobutane-diamide compound with antitumor activity and preparation method and application thereof Download PDFInfo
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- CN105859638A CN105859638A CN201610280785.1A CN201610280785A CN105859638A CN 105859638 A CN105859638 A CN 105859638A CN 201610280785 A CN201610280785 A CN 201610280785A CN 105859638 A CN105859638 A CN 105859638A
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- 0 C*c1cccc(NC(C2(CCC2)C(Nc(cc2)ccc2-c(cc2N=CN3)ccc2C3=O)=O)=O)c1 Chemical compound C*c1cccc(NC(C2(CCC2)C(Nc(cc2)ccc2-c(cc2N=CN3)ccc2C3=O)=O)=O)c1 0.000 description 2
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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 invention provides a cyclobutane-diamide compound with antitumor activity and a preparation method and application thereof. The structure formula of the compound is shown in the description, wherein R1 and R2 are hydrogen, alkane groups or halogen groups. The compound has very good inhibitory activity for VEGFR-2 kinase and can cut off an inductive signal channel of the VEGFR-2 kinase and restrain hyperplasia and migration of tumor cells by restraining the activity of the VEGFR-2 kinase, and therefore the compound can be applied to preparation of antitumor drugs. The preparation method of the compound has the advantages that raw materials are easy to get, reaction conditions are mild, operation is easy in the reaction process, and adopted reagents are low in price.
Description
Technical field
The invention belongs to biomedicine technical field, relate to a kind of antineoplastic compound, particularly to one, there is anti-tumor activity
Ring succinamide compound and its preparation method and application.
Background technology
Malignant tumor, as one of bigger public health problem in the whole world, greatly endangers the health of the mankind, and will become new century people
First killer of class.Malignant tumor is the most no longer the serious disease of advanced industrial country, and developing country is faced with bigger disease
Burden.Chemotherapy, as one of important means treating tumor, has had huge development and progress at nearly 30 years,
Obtain large quantities of clinical antitumor agents with different mechanism of action.But antineoplastic agent there is also many untoward reaction, such as
Alopecia, vomiting, produce bone marrow depression, quickly produce drug resistance etc., these result in chemicals and are unable to reach intended treatment
Effect.The research and development of the newest antitumor drug are one of focus and difficulties of current pharmaceutical field.
Summary of the invention
It is an object of the invention to provide a kind of ring succinamide compound with anti-tumor activity and its preparation method and application, should
Compound embodies good anti-tumor activity in vitro, it is possible to be applied to the preparation of antitumor drug.
For reaching above-mentioned purpose, the present invention by the following technical solutions:
A kind of ring succinamide compound with anti-tumor activity, its chemical structural formula is as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.
Described halogen group is fluorine atom, chlorine atom, bromine atoms or trifluoromethyl.
Described alkane group is methyl or ethyl.
The preparation method of the described ring succinamide compound with anti-tumor activity, comprises the following steps:
1) 2-amino-4-bromobenzoic acid and Methanamide prepare 7-bromine quinazoline-4 (3H)-one by ring-closure reaction；
2) under the catalytic action of tetrakis triphenylphosphine palladium, 7-bromine quinazoline-4 (3H)-one is passed through with p-aminophenyl borate hydrochlorate
Suzuki reaction obtains biphenol compound；
3) to occur acylation reaction to obtain under the conditions of thionyl chloride monoacylated for 1,1 cyclobutyl dioctyl phthalate and monosubstituted or disubstituted aniline
Fourth formic acid；
4) biphenol compound and monoacylated fourth formic acid generate the ring with anti-tumor activity under the condensation of HATU condensing agent
Succinamide compound.
Described step 1) concrete operations be: 2-amino-4-bromobenzoic acid is dissolved in Methanamide, reacts under nitrogen protection,
After reaction terminates, being added by reactant liquor in frozen water, be extracted with ethyl acetate, the decompression scrubbed, dried of the organic facies of extraction boils off
Solvent, obtains rufous residue, with chromatographic column separation rufous residue, obtain red brown solid 7-bromine quinazoline-4 (3H)-
Ketone.
Described step 2) concrete operations be: by 7-bromine quinazoline-4 (3H)-one, p-aminophenyl borate hydrochlorate, Anhydrous potassium carbonate
With in the mixed solution that tetrakis triphenylphosphine palladium is dissolved in Isosorbide-5-Nitrae-dioxane and water, reacting under nitrogen protection, reaction cools down after terminating
To room temperature, being extracted with ethyl acetate, the decompression scrubbed, dried of the organic facies of extraction boils off solvent, obtains crude product, divides with chromatographic column
From crude product, obtain biphenol compound.
Described step 3) concrete operations be: under nitrogen protection, anhydrous triethylamine is added drop-wise to 1, the nothing of 1 cyclobutyl dioctyl phthalate
In water tetrahydrofuran solution, under condition of ice bath, stirring reaction, drips the anhydrous tetrahydrofuran solution of thionyl chloride the most wherein, stirs
Mix reaction, then drip the anhydrous tetrahydrofuran solution of monosubstituted or disubstituted aniline wherein, stirring reaction, after reaction terminates,
Washed by reactant liquor, dried decompression boils off solvent, obtains crude product, with chromatographic column separation crude product, obtains monoacylated fourth formic acid.
Described step 4) concrete operations be: under condition of ice bath, biphenol compound and monoacylated fourth formic acid are joined anhydrous
In oxolane, add HATU, stirring reaction, be then added thereto to the tetrahydrofuran solution of anhydrous triethylamine, remove ice
Bath, reacts under room temperature, after reaction terminates, is extracted with ethyl acetate, and the decompression scrubbed, dried of the organic facies of extraction boils off solvent,
Obtain crude product, with chromatographic column separation crude product, obtain the ring succinamide compound with anti-tumor activity.
The described ring succinamide compound with anti-tumor activity answering in the medicine of preparation suppression VEGFR-2 kinase activity
With.
The described ring succinamide compound with anti-tumor activity is preparing the antitumor drug with VEGFR-2 kinases as target spot
In application.
Compared with prior art, the method have the advantages that
The ring succinamide compound with anti-tumor activity that the present invention provides, is a kind of novel chemical combination with anti-tumor activity
Thing, it has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antitumor drug.Concrete, the present invention provides
The ring succinamide compound with anti-tumor activity, it is possible to suppression the kinase whose activity of VEGFR-2.And angiogenesis and tumor
Generation, develop and migrated substantial connection, the formation of suppression new vessels can effectively suppress growth and the migration of tumor,
Many somatomedin regulation and control new vesselses generate, and wherein VEGFR-2 is the strongest known positive regulatory factor.Therefore the present invention carries
The ring succinamide compound with anti-tumor activity of confession, by the suppression kinase whose activity of VEGFR-2, blocks the signal of its induction
Path, the hypertrophy of suppression tumor cell and migration, thus can be applicable to the preparation of antitumor drug, especially swash with VEGFR-2
Enzyme is antitumor drug and the medicine of suppression VEGFR-2 kinase activity of target spot.
The preparation method of the ring succinamide compound with anti-tumor activity that the present invention provides, by 2-amino-4-bromobenzoic acid
Obtain 7-bromine quinazoline-4 (3H)-one with formamide, then react with p-aminophenyl borate hydrochlorate and obtain biphenol compound, and
By 1,1 cyclobutyl dioctyl phthalate obtains monoacylated fourth formic acid, by the substituent group in aniline with monosubstituted or disubstituted aniline reaction
Being incorporated on monoacylated fourth formic acid, then biphenol compound carries out condensation reaction with monoacylated fourth formic acid again, i.e. obtains having anti-
The ring succinamide compound of tumor promotion, the method has raw material and is easy to get, and reaction condition is gentle, and course of reaction is simple to operate, institute
By the cheap advantage of reagent.
Accompanying drawing explanation
The synthetic route chart of the ring succinamide compound with anti-tumor activity that Fig. 1 provides for the present invention；
Wherein, compound 1 is 2-amino-4-bromobenzoic acid, and compound 2 is 7-bromine quinazoline-4 (3H)-one, and compound 3 is right
Aminobenzene borate hydrochlorate, compound 4 is biphenol compound；Compound is 5 to be 1,1 cyclobutyl dioctyl phthalate, and compound 6 is single
Replacing or disubstituted aniline, compound 7 is monoacylated fourth formic acid, and compound 8 is the ring succinamide with anti-tumor activity
Compound.
In figure mark particularly as follows:
a.HCONH2,MW,150℃；b.Pd(PPh3)4,K2CO3,H2O,dioxane,100℃；c.SOCl2,Et3N,DCM,0℃；
d.HATU,Et3N,THF,rt.
Detailed description of the invention
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, described in be explanation of the invention and not
It is to limit.
The invention provides a kind of ring succinamide compound with anti-tumor activity, this ring succinamide compound has in vitro
Anti-tumor activity, can be applicable to the preparation of antitumor drug.
Containing quinazolinone group in the structural formula of the ring succinamide compound with anti-tumor activity that the present invention provides, its chemistry
Structural formula is specific as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.Described halogen group is fluorine atom, chlorine atom, bromine atoms
Or trifluoromethyl.
Having of present invention offer is described in detail anti-swollen below in conjunction with the synthetic route shown in Fig. 1 and concrete synthetic example
The preparation of the drug candidate ring succinamide compound of tumor activity and method for screening active ingredients.
Embodiment 1
This has in the structural formula of ring succinamide compound of anti-tumor activity, R1For hydrogen, R2For F, prepared by following steps
(seeing Fig. 1):
1) 2-amino-4-bromobenzoic acid (compound 1) prepares (change of 7-bromine quinazoline-4 (3H)-one with Methanamide by ring-closure reaction
Compound 2)
5.0g (23.14mmol) 2-amino-4-bromobenzoic acid is dissolved in 80ml (2.01mmol) Methanamide, nitrogen protection under
150 DEG C, power be 300W microwave condition under react 1.45h, reaction terminate after, reactant liquor is added in frozen water, uses acetic acid second
Ester extracts 3-4 time, and the organic facies of extraction is washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively, then does with anhydrous sodium sulfate
Dry, then it is spin-dried for, obtains rufous residue, with chromatographic column separation rufous residue, obtain red brown solid 7-bromine quinazoline
-4 (3H)-one 1.89g, productivity 36.3%.
2) by 7-bromine quinazoline-4 (3H)-one (compound 2) and p-aminophenyl boric acid hydrochloric acid under tetrakis triphenylphosphine palladium catalytic reaction
Salt (compound 3) obtains 4 ((3H)-7-quinazoline-4-one) aniline (compound 4) by Suzuki reaction；
By 0.87g (3.87mmol) 7-bromine quinazoline-4 (3H)-one, 0.61g (3.52mmol) p-aminophenyl borate hydrochlorate, 1.46g
(10.56mmol) Anhydrous potassium carbonate and 0.4g (0.35mmol) tetrakis triphenylphosphine palladium are dissolved in 90mL 1,4-dioxane and 30mL water
In mixed solution, under nitrogen protection in 100 DEG C of reactions overnight, reaction is cooled to room temperature after terminating, and is extracted with ethyl acetate, extraction
The organic facies taken decompression scrubbed, dried boils off solvent, obtains crude product, with chromatographic column separation crude product, obtains yellow solid 4 ((3H)-7-
Quinazoline-4-one) aniline 0.72g, productivity 85.7%.
3) there is acylation reaction in 1,1 cyclobutyl dioctyl phthalate (compound 5) and m-fluoroaniline (compound 6) under the conditions of thionyl chloride
Obtain 1-((3-fluorophenyl) carbamyl) ring fourth formic acid (compound 7)；
Under nitrogen protection, 1ml (6.94mmol) anhydrous triethylamine is slowly dropped to 1g (6.94mmol) 1,1 cyclobutyl dioctyl phthalate
In anhydrous tetrahydrofuran solution 20ml, stirring reaction 30min under condition of ice bath, continues to drip slow 0.5ml the most wherein
(6.94mmol) the anhydrous tetrahydrofuran solution 5ml of thionyl chloride, stirring reaction 2 hours, then it is slowly added dropwise 0.77g wherein
(6.94mmol) the anhydrous tetrahydrofuran solution 20ml of m-fluoroaniline, stirring reaction 2 hours, after reaction terminates, reactant liquor is washed,
Dried decompression boils off solvent, obtains crude product, with chromatographic column separation crude product, obtains white solid 1-((3-fluorophenyl) carbamyl) ring
Fourth formic acid 0.51g, productivity 30.9%.
4) 4 ((3H)-7-quinazoline-4-one) aniline (compounds 4) and 1-((3-fluorophenyl) carbamyl) ring fourth formic acid (compound 7)
Target compound (compound 8) is generated under HATU condensing agent is condensed.
Under condition of ice bath, by 0.13g (0.53mmol) 4 ((3H)-7-quinazoline-4-one) aniline and 0.19g (0.80mmol) 1-((3-fluorine
Phenyl) carbamyl) ring fourth formic acid joins in 15ml anhydrous tetrahydro furan, adds 0.36g (0.95mmol) HATU, stirring
It is slowly added to the tetrahydrofuran solution 3ml of 0.07ml (0.53mmol) anhydrous triethylamine after reaction 30min, removes ice bath, under room temperature
Reactant liquor overnight, after reaction terminates, is extracted with ethyl acetate by reaction, and the decompression scrubbed, dried of the organic facies of extraction boils off molten
Agent, obtains crude product, with chromatographic column separation crude product, obtains target compound 0.18g, productivity 75.0%.
The structure of gained target compound is as follows:
Physicochemical property: mp: > 300 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR (400MHz, DMSO) δ 9.87 (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 spectrum nuclear magnetic resonance data is: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
This has in the structural formula of ring succinamide compound of anti-tumor activity, R1、R2It is trifluoromethyl.
Step 1)～step 3) with the step 1 in embodiment 1)～step 3) identical, i.e. by initial compounds 2-amino-4-bromine
Benzoic acid (compound 1) and Methanamide prepare 7-bromine quinazoline-4 (3H)-one (compound 2), 7-bromine quinazoline by ring-closure reaction
-4 (3H)-one (compound 2) and p-aminophenyl borate hydrochlorate (compound 3) are reacted by Suzuki and obtain 4 ((3H)-7-quinoline azoles
Quinoline-4-ketone) aniline (compound 4), 1,1 cyclobutyl dioctyl phthalate (compound 5) and 3,5-bis-5-trifluoromethylaniline (compound 6)
Acylation reaction is occurred to obtain 1-((3,5-bis-trifluoromethyl) carbamyl) ring fourth formic acid (compound 7) under the conditions of thionyl chloride.
4) 4 ((3H)-7-quinazoline-4-one) aniline (compounds 4) and 1-((3,5-bis-trifluoromethyl) carbamyl) ring fourth formic acid
(compound 7) generates target compound (compound 8) under HATU condensing agent is condensed, and concrete operating procedure is:
Under condition of ice bath, by 0.45g (1.88mmol) 4 ((3H)-7-quinazoline-4-one) aniline and 1.00g (2.81mmol) 1-((3,5-
Two trifluoromethyls) carbamyl) ring fourth formic acid joins in 30ml anhydrous tetrahydro furan, adds 2.14g (5.64mmol)
HATU, is slowly added to the tetrahydrofuran solution 20ml of 0.78ml (5.64mmol) anhydrous triethylamine, removes after stirring reaction 30min
Ice bath, reacts under room temperature overnight, after reaction terminates, is extracted with ethyl acetate by reactant liquor, and the organic facies of extraction is scrubbed, dry
Rear decompression boils off solvent, obtains crude product, with chromatographic column separation crude product, obtains target compound 0.23g, productivity 21.3%.
The structure of gained target compound is as follows:
Physicochemical property: mp: > 300 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is: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 spectrum nuclear magnetic resonance data is: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
This has in the structural formula of ring succinamide compound of anti-tumor activity, R1For chlorine, R2For CH3。
Step 1)～step 3) with the step 1 in embodiment 1)～step 3) identical, i.e. by initial compounds 2-amino-4-bromine
Benzoic acid (compound 1) and Methanamide prepare 7-bromine quinazoline-4 (3H)-one (compound 2), 7-bromine quinazoline by ring-closure reaction
-4 (3H)-one (compound 2) and p-aminophenyl borate hydrochlorate (compound 3) are reacted by Suzuki and obtain 4 ((3H)-7-quinoline azoles
Quinoline-4-ketone) aniline (compound 4), 1,1 cyclobutyl dioctyl phthalate (compound 5) and 3-chloro-4-monomethylaniline. (compound 6) are at chlorine
Acylation reaction is occurred to obtain 1-((3-chloro-4-aminomethyl phenyl) carbamyl) ring fourth formic acid (compound 7) under the conditions of changing sulfoxide.
4) 4 ((3H)-7-quinazoline-4-one) aniline (compounds 4) (are changed with 1-((3-chloro-4-aminomethyl phenyl) carbamyl) ring fourth formic acid
Compound 7) under HATU condensing agent is condensed, generate target compound (compound 8), concrete operating procedure is:
Under condition of ice bath, by 0.59g (2.49mmol) 4 ((3H)-7-quinazoline-4-one) aniline and 1.00g (3.74mmol) 1-((3-chlorine
-4-aminomethyl phenyl) carbamyl) ring fourth formic acid joins in 30ml anhydrous tetrahydro furan, adds 2.84g (7.47mmol) HATU,
It is slowly added to the tetrahydrofuran solution 20ml of 01.00ml (7.47mmol) anhydrous triethylamine after stirring reaction 30min, removes ice bath,
Reacting overnight under room temperature, after reaction terminates, be extracted with ethyl acetate by reactant liquor, the organic facies of extraction is scrubbed, reduce pressure after drying
Boil off solvent, obtain crude product, with chromatographic column separation crude product, obtain target compound 0.25g, productivity 20.7%.
The structure of gained target compound is as follows:
Physicochemical property: mp: > 300 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is: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 spectrum nuclear magnetic resonance data is: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 ring succinamide compound with anti-tumor activity prepared the present invention below carries out the kinase whose inhibitory activity of VEGFR-2
Screening.
The ring succinamide compound pair with anti-tumor activity prepared by the HTRF KinEASE kit measurement present invention
The inhibitory activity of VEGFR-2: use the Lance experiment detection ring succinamide compound inhibitory activity to VEGFR-2, operation
Method illustrates to carry out according to test kit.Adding in 384 orifice plates by the substrate of 2 μ L kinases and 2 μ L, VEGFR-2 concentration is
0.09ng/ μ L, concentration of substrate is 180nM.It is subsequently adding substrate polypeptide and the 4 μ L testing compounds of variable concentrations, adds 2
μ L ATP starts reaction, after reacting 30min, adds EDTA and terminates reaction at 37 DEG C.Reaction terminates to divide in backward reactant liquor
Do not add Eu3+The antibody of-cryptate labelling and streptavidin-XL665, at room temperature hatch 1h, uses
Perkin-Elmer Victor 5 measures absorbance, kinase activity A665/A615 × 10 under 665nm and 615nm wavelength respectively4
Characterize, calculate the ring succinamide compound with anti-tumor activity that the present invention provides to the suppression ratio of VEGFR-2 and IC50。
Ring succinamide compound inhibitory activity kinase whose to the VEGFR-2 result such as table with anti-tumor activity that the present invention provides
Shown in 1:
The VEGFR-2 inhibitory activity of table 1 ring succinamide compound
As can be seen from Table 1, what prepared by the present invention has the ring succinamide compound of anti-tumor activity to VEGFR-2 kinases tool
There is inhibitory activity, can be used for the medicine of preparation suppression VEGFR-2 kinase activity and prepare with VEGFR-2 kinases as target spot
Antitumor drug.
Ring succinamide preferable to VEGFR-2 kinase inhibitory effect in the above-mentioned ring succinamide compound with anti-tumor activity
The concrete structure of compound is as shown in table 2.
The structural formula of table 2 ring succinamide compound
Claims (10)
1. a ring succinamide compound with anti-tumor activity, it is characterised in that its chemical structural formula is as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.
There is the ring succinamide compound of anti-tumor activity the most as claimed in claim 1, it is characterised in that described halogen
Group is fluorine atom, chlorine atom, bromine atoms or trifluoromethyl.
There is the ring succinamide compound of anti-tumor activity the most as claimed in claim 1, it is characterised in that described alkane
Group is methyl or ethyl.
4. the preparation method of the ring succinamide compound with anti-tumor activity described in any one in claim 1-3, its
It is characterised by, comprises the following steps:
1) 2-amino-4-bromobenzoic acid and Methanamide prepare 7-bromine quinazoline-4 (3H)-one by ring-closure reaction；
2) under the catalytic action of tetrakis triphenylphosphine palladium, 7-bromine quinazoline-4 (3H)-one is passed through with p-aminophenyl borate hydrochlorate
Suzuki reaction obtains biphenol compound；
3) to occur acylation reaction to obtain under the conditions of thionyl chloride monoacylated for 1,1 cyclobutyl dioctyl phthalate and monosubstituted or disubstituted aniline
Fourth formic acid；
4) biphenol compound and monoacylated fourth formic acid generate the ring with anti-tumor activity under the condensation of HATU condensing agent
Succinamide compound.
5. the preparation method of the ring succinamide compound with anti-tumor activity described in 4 is wanted according to right, it is characterised in that:
Described step 1) concrete operations be: 2-amino-4-bromobenzoic acid is dissolved in Methanamide, reacts under nitrogen protection, instead
After should terminating, being added by reactant liquor in frozen water, be extracted with ethyl acetate, the decompression scrubbed, dried of the organic facies of extraction boils off molten
Agent, obtains rufous residue, with chromatographic column separation rufous residue, obtains red brown solid 7-bromine quinazoline-4 (3H)-one.
6. the preparation method of the ring succinamide compound with anti-tumor activity described in 4 is wanted according to right, it is characterised in that:
Described step 2) concrete operations be: by 7-bromine quinazoline-4 (3H)-one, p-aminophenyl borate hydrochlorate, Anhydrous potassium carbonate and four
(triphenylphosphine) palladium is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, reacts under nitrogen protection, and reaction is cooled to room after terminating
Temperature, is extracted with ethyl acetate, and the decompression scrubbed, dried of the organic facies of extraction boils off solvent, obtains crude product, separates thick with chromatographic column
Product, obtain biphenol compound.
7. the preparation method of the ring succinamide compound with anti-tumor activity described in 4 is wanted according to right, it is characterised in that:
Described step 3) concrete operations be: under nitrogen protection, anhydrous triethylamine is added drop-wise to 1, anhydrous the four of 1 cyclobutyl dioctyl phthalate
In hydrogen tetrahydrofuran solution, stirring reaction under condition of ice bath, drip the anhydrous tetrahydrofuran solution of thionyl chloride the most wherein, stirring is anti-
Answer, then drip the anhydrous tetrahydrofuran solution of monosubstituted or disubstituted aniline wherein, stirring reaction, after reaction terminates, will be instead
Answer liquid washing, dried decompression to boil off solvent, obtain crude product, with chromatographic column separation crude product, obtain monoacylated fourth formic acid.
8. the preparation method of the ring succinamide compound with anti-tumor activity described in 4 is wanted according to right, it is characterised in that:
Described step 4) concrete operations be: under condition of ice bath, biphenol compound and monoacylated fourth formic acid are joined anhydrous tetrahydrochysene
In furan, add HATU, stirring reaction, be then added thereto to the tetrahydrofuran solution of anhydrous triethylamine, remove ice bath,
Reacting under room temperature, after reaction terminates, be extracted with ethyl acetate, the decompression scrubbed, dried of the organic facies of extraction boils off solvent,
Crude product, with chromatographic column separation crude product, obtains the ring succinamide compound with anti-tumor activity.
9. in claim 1-3 the ring succinamide compound with anti-tumor activity described in any one in preparation suppression
Application in the medicine of VEGFR-2 kinase activity.
10. in claim 1-3 the ring succinamide compound with anti-tumor activity described in any one preparation with
VEGFR-2 kinases is the application in the antitumor drug of target spot.
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| CN105859638B CN105859638B (en) | 2018-07-17 |
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| CN105175351A (en) * | 2014-05-30 | 2015-12-23 | 中国科学院上海药物研究所 | 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof |
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| WO2012047017A2 (en) * | 2010-10-05 | 2012-04-12 | 크리스탈지노믹스(주) | 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same |
| CN105175351A (en) * | 2014-05-30 | 2015-12-23 | 中国科学院上海药物研究所 | 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof |
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| XIAOLONG JIANG，ET AL.: "Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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