CN109761968A - Paeonol with anti-tumor activity and benzoxazine compounds and its preparation method and application - Google Patents
Paeonol with anti-tumor activity and benzoxazine compounds and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of Paeonol with anti-tumor activity and benzoxazine compounds and its preparation method and application, belong to the synthesis technical field of anti-tumor drug.Technical solution of the present invention main points are as follows: Paeonol with anti-tumor activity and benzoxazine compounds, structural formula are as follows:
Description
Technical field
The invention belongs to the synthesis technical fields of lung cancer and treatment of human cervical cancer drug, and in particular to one kind has antitumor work
Property Paeonol and benzoxazine compounds and its preparation method and application.
Background technique
Cortex moutan is my distinctive resource, is recorded according to Compendium of Material Medica, cortex moutan acrid flavour is cold, without product, cure mainly fever and chills, apoplexy
Disease, frightened pain perverse trend, five viscera settling treat pain sore, long term usage fat reducing and long life.Paeonol (Paeonol) is also known as paeonol, is ranunculaceae plant
The principle active component of moutan root bark, the content in moutan root bark account for about the 4%-7.5% of root skin weight.The molecule of Paeonol
Formula is C9H10O3, chemical name is Paeonolum, and chemical structural formula is as follows, and molecular weight is
166.18, it is a kind of phenolic compound of small molecule that fusing point, which is 51 ± 1 DEG C, in from color acicular crystal, has low melting point, Yi Hui
The characteristics such as hair and poorly water-soluble.
The chemical structural formula of Paeonol
Recent studies indicate that Paeonol have antipyretic, analgesia, anti-oxidant, anti-arrhythmia, anti-atherosclerosis,
Improve microcirculation, protection ischemic tissue, strengthen immunity, antibacterial, it is antitumor the effects of.Modern age pharmacology and clinical research are pointed out:
(1) there is Paeonol treatment hypertension and protection ischemic the active effect of SOD of heart tissue is perfused；(2) Paeonol absorbed can make hair
Thin blood vessel dilatation accelerates red blood cell velocity, so as to improve local circulation；(3) Paeonol is to Escherichia coli, streptococcus, withered grass bar
Bacterium, staphylococcus aureus etc. have apparent effect；(4) inhibit erythrocyte infiltration and haemolysis, increase body non-specificity and exempt from
Epidemic disease；(5) Paeonol includes that its is good for the curative effects such as eczema, dermatitis, nettle rash to multiple dermatosis, in medicine, fragrance, chemical field
Tool has been widely used, and is used for a variety of daily cosmetics, toothpaste, women and infant hygiene articles, food additives etc..With
Synthesis and pharmacological action to Paeonol and its derivative are constantly furtherd investigate, and the clinic of Paeonol has greatly been pushed to make
With.
Meter spring swallow detects and observes the synergistic effect of Paeonol and chemotherapeutics using thiazolyl blue (MTT) method, finds the root bark of tree peony
Phenol can effectively inhibit HT-29 cell Proliferation, and be in positive dependence with drug concentration and action time；The root bark of tree peony of low concentration
Phenol cooperates with medication with chemotherapeutics, can produce stronger Inhibit proliferaton effect, shows that Paeonol has direct antineoplastic action,
Low concentration Paeonol and chemotherapeutics have synergistic effect.Sun Guoping is using mtt assay detection Paeonol to the tumour of in vitro culture
The inhibited proliferation of cell, the results showed that the inhibiting effect of Paeonol enhances with increasing for drug concentration, there is apparent agent
Measure structure-activity relationship；It has also been found that Paeonol has an apparent time relationship to the inhibited proliferation of cancer cell, the extension of action time,
Inhibiting effect is also stronger.
According to drug principle of hybridization, two or more segments with different bioactivity are connected in the same molecule
The drug molecule for designing synthesis can be by combining different biological targets to play good drug action.Principle accordingly will have
There is the benzoxazine ring of bioactivity to be linked into Paeonol by cycloaddition reaction, synthesizes a series of Paeonols and benzoxazine
Class compound finds synthesized Paeonol and benzoxazine compounds all has than pellet through preliminary biological activity test
The better anti-tumor activity of skin phenol, these compounds can be used for inhibiting Non-small cell lung carcinoma cell NCI-H1299 cell and
The growth of HeLa Cells, thus vital promotion is played to the treatment of human research's adenocarcinoma of lung and cervical carcinoma
Effect, makes it have broad application prospects in field of medicaments.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of Paeonol with anti-tumor activity and benzoxazine classes
Close object.
There is provided a kind of easy to operate, mild, easily controllable and mesh of reaction for another technical problem that the present invention solves
Mark the preparation method of the higher Paeonol with anti-tumor activity of product yield and benzoxazine compounds.
There is provided Paeonol with anti-tumor activity and benzoxazine class chemical combination for the technical issues of present invention also solves
Application of the object in preparation treatment mankind's adenocarcinoma of lung or/and uterine neck cancer drug.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, Paeonol with anti-tumor activity and benzo
Oxazine compound, it is characterised in that its structural formula are as follows:Wherein R is phenyl, takes
For phenyl or naphthyl, the substituent group on the substituted-phenyl phenyl ring is halogen atom, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl-carbonyl,
Nitro or hydroxyl, n are any one integer between 0~4.
The preparation method of Paeonol with anti-tumor activity of the present invention and benzoxazine compounds, feature
It is specific steps are as follows:
The synthesis of step S1:1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone
Paeonol and the concentrated sulfuric acid are placed in reaction vessel, in -15 DEG C of dropwise addition concentrated nitric acids, in room temperature reaction after being added dropwise
Product 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone is made；
The synthesis of step S2:1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone
1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone and glacial acetic acid are placed in reaction vessel, after its dissolution
Zinc powder is added under the conditions of ice-water bath, reaction is stirred at room temperature, product 1- (3- amino -2- hydroxyl -4- methoxyphenyl) second is made
Ketone；
The synthesis of step S3:8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one
8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] (4H) -one of oxazines -3 and dichloroethanes are placed in reaction to hold
In device, in 0 DEG C of addition chloracetyl chloride, TLC monitors it and is spin-dried for solvent after completion of the reaction, DMF and Anhydrous potassium carbonate is added, in room temperature
It reacts and product 8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one is made；
Step S4:8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
Synthesis
By 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one, 3- bromine third
Alkynes, Anhydrous potassium carbonate and DMF are placed in reaction vessel, and product 8- acetyl group -5- methoxyl group -4- (propyl- 2- is made in reacting at room temperature
Alkynyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one；
Step S5: the synthesis of Paeonol and benzoxazine compounds
8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] evil is sequentially added in the reactor
The mixed solution, azidomethyl phenyl nitrogen compound and sodium ascorbate of piperazine -3 (4H) -one, the tert-butyl alcohol and water, add catalyst Cu
(CH3COO)2·H2Target product Paeonol and benzoxazine compounds are made in reacting at room temperature in O.
The preparation method of Paeonol with anti-tumor activity of the present invention and benzoxazine compounds, feature
It is specific steps are as follows:
The synthesis of step S1:1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone
120mmol Paeonol and the 100mL concentrated sulfuric acid are placed in the reaction flask of 500mL, in -15 DEG C of dense nitre of dropwise addition 5.4mL
Acid, in room temperature reaction after being added dropwise, to end of reaction, reaction solution is poured into 500mL ice water, is filtered for TLC monitoring reaction,
Filter cake is dried, column chromatographic purifying obtains yellow solid 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone 5.91g, and yield is
23%；
The synthesis of step S2:1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone
25mmol 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone and 25mL glacial acetic acid are placed in the anti-of 100mL
It answers in bottle, 0.25mol zinc powder is added in ice-water bath after its dissolution, reaction, TLC monitoring reaction, wait react is stirred at room temperature
It finishes, neutralization reaction, ethyl acetate extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains ginger-colored graininess
Powder solid 1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone 2.62g, yield 58%；
The synthesis of step S3:8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one
By 15mmol 8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] (4H) -one of oxazines -3 and 40mL dichloroethanes
It is placed in the reaction flask of 100mL, in 0 DEG C of addition 16.5mmol chloracetyl chloride, TLC monitors it and is spin-dried for solvent after completion of the reaction, adds
Entering 30mL DMF and 18mmol Anhydrous potassium carbonate in room temperature reaction, TLC monitoring reaction washes DMF three times to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains white solid 8- acetyl group -5- methoxyl group -
2H- benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one 2.84g, yield 86%；
Step S4:8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
Synthesis
By 10mmol 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -
Ketone, 12mmol 3- propargyl bromide, 12mmol Anhydrous potassium carbonate and 20mL DMF are placed in 100mL reaction flask in room temperature reaction, TLC
Monitoring reaction washes DMF three times to end of reaction, and ethyl acetate extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatography is pure
Change obtains white solid 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
2.51g, yield 97%；
Step S5: the synthesis of Paeonol and benzoxazine compounds
0.5mmol 8- acetyl group -5- methoxyl group -4- (Propargyl)-is sequentially added in the stand up reaction bottle of 25mL
The mixed solution, 0.6mmol azidomethyl phenyl nitrogen compound of 2H- benzo [b] [1,4] oxazines -3 (4H) -one, the 2mL tert-butyl alcohol and water
With 0.1mmol sodium ascorbate, 0.05mmol catalyst Cu (CH is then added3COO)2·H2O, in room temperature reaction, TLC monitoring
Reaction is spin-dried for solvent, methylene chloride extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains to end of reaction
Target product Paeonol and benzoxazine compounds.
Further preferably, the volume ratio of the tert-butyl alcohol and water is 1:1 in the mixed solution of the tert-butyl alcohol described in step S5 and water.
Simultaneously benzoxazine compounds are being prepared for inhibiting people Paeonol with anti-tumor activity of the present invention
Application in the growth of non-small cell lung cancer cell NCI-H1299 cell or/and HeLa Cells growth drug.
By " Click Chemistry ", to Paeonol, simultaneously benzoxazine is chemically modified the present invention, will be had anti-swollen
The 1 of tumor activity, 2,3- triazole rings are introduced into Paeonol, have synthesized 18 kinds of Paeonols and benzoxazine compounds, these changes
Closing object can inhibit the growth of Non-small cell lung carcinoma cell NCI-H1299 cell and HeLa Cells, thus promote
Research of the mankind to adenocarcinoma of lung and cervical carcinoma.
Specific embodiment
It is to be done further specifically by the specific embodiment of embodiment form to above content of the invention below
It is bright, but this should not be interpreted as to the scope of the above subject matter of the present invention is limited to the following embodiments, it is all above-mentioned based on the present invention
The technology that content is realized all belongs to the scope of the present invention.
Embodiment 1
8- acetyl group -5- methoxyl group -4- ((1- phenyl -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo [b] [1,4]
The synthesis of oxazines -3 (4H) -one
The synthesis of step S1:1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone
Paeonol (120mmol, 19.94g) and the 100mL concentrated sulfuric acid are placed in the reaction flask of 500mL, slowly in -15 DEG C
It is added dropwise concentrated nitric acid (120mmol, 5.4mL), in room temperature reaction after being added dropwise, TLC monitoring reaction to end of reaction, will react
Liquid pours into 500mL ice water, filters, and dries filter cake, and column chromatographic purifying (volume ratio: PE/EA=4:3) obtains yellow solid
5.91g, yield 23%；1H NMR(400MHz,DMSO-d6) δ 13.05 (s, 1H, OH), 8.17 (d, J=9.1Hz, 1H, Ar-
), H 6.93 (d, J=9.1Hz, 1H, Ar-H), 4.00 (s, 3H, CH3),2.65(s,3H,CH3)；13C NMR(100MHz,DMSO-
d6)δ204.7,156.4,154.4,135.7,130.4,114.8,104.25,57.9,27.2。
The synthesis of step S2:1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone
1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone (25mmol, 5.66g) and 25mL glacial acetic acid are placed in
In the reaction flask of 100mL, after its dissolution, zinc powder (0.25mol, 16.35g) is slowly added under the conditions of ice-water bath, in room temperature
It is stirred to react, TLC monitoring reaction, to end of reaction, neutralization reaction, ethyl acetate extraction, anhydrous sodium sulfate is dry, filters rotation
Dry, column chromatographic purifying (PE/EA=4:3, volume ratio) obtains ginger-colored particulate powder solid 2.62g, yield 58%；1H
NMR(400MHz,CDCl3) δ 12.46 (s, 1H, OH), 7.19 (d, J=8.9Hz, 1H, Ar-H), 6.45 (d, J=8.9Hz, 1H,
Ar-H),3.92(s,4H,CH3),3.84(s,2H,NH2),2.56(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ203.5,
151.9,150.5,124.3,120.6,114.4,102.1,55.8,26.3。
The synthesis of step S3:8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one
By 8- acetyl group -5- methoxyl group -2H- benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (15mmol, 2.72g) and 40mL
Dichloroethanes is placed in the reaction flask of 100mL, and in 0 DEG C of addition chloracetyl chloride (16.5mmol, 1.23mL), TLC monitors its reaction
After, it is spin-dried for solvent, 30mL DMF and Anhydrous potassium carbonate (18mmol, 2.49g) is added, in room temperature reaction, TLC monitoring is anti-
It answers, to end of reaction, washes DMF three times, methylene chloride extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, column chromatographic purifying (body
Product ratio: PE/EA=5:1) obtain white solid 2.84g, yield 86%；1H NMR(400MHz,CDCl3)δ7.98(s,1H,
), NH 7.56 (d, J=8.9Hz, 1H, Ar-H), 6.63 (d, J=8.9Hz, 1H, Ar-H), 4.69 (s, 2H, CH2),3.94(s,
3H,CH3),2.58(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.3,163.5,149.8,144.3,125.4,
120.9,115.8,104.7,67.1,56.3,31.6。
Step S4:8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
Synthesis
By 8- acetyl group -5- methoxyl group -2H- benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (10mmol, 2.21g), 3- bromine third
Alkynes (12mmol, 1.43g), Anhydrous potassium carbonate (12mmol, 1.66g) and 20mL DMF are placed in 100mL reaction flask, at room temperature
Reaction, TLC monitoring reaction wash DMF three times to end of reaction, and ethyl acetate extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for,
Column chromatographic purifying (volume ratio: PE/EA=5:1) obtains white solid 2.51g, yield 97%；1H NMR(400MHz,CDCl3)
δ 7.66 (d, J=9.0Hz, 1H, Ar-H), 6.74 (d, J=9.0Hz, 1H, Ar-H), 4.87 (d, J=2.4Hz, 2H, CH2),
4.58(s,2H,CH2),3.96(s,3H,CH3),2.59(s,3H,CH3), 2.12 (t, J=2.4Hz, 1H, CH)；13C NMR
(100MHz,CDCl3)δ196.4,165.0,153.6,149.9,127.3,121.3,117.9,106.6,78.4,71.5,
68.5,56.3,34.1,31.7。
Embodiment 2
8- acetyl group -5- methoxyl group -4- ((1- phenyl -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo [b] [1,4]
The synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 1- triazobenzene of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water
Catalyst Cu (CH is then added in (0.6mmol, 0.0715g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·H2O
(0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent, methylene chloride extraction, nothing to end of reaction
Aqueous sodium persulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 99.1mg, yield 52.4%.1H NMR
(400MHz,CDCl3) δ 7.94 (s, 1H, CH), 7.67 (d, J=8.0Hz, 2H, Ar-H), 7.61 (d, J=9.2Hz, 1H, Ar-
), H 7.47 (t, J=7.8Hz, 2H, Ar-H), 7.39 (t, J=7.4Hz, 1H, Ar-H), 6.69 (d, J=8.8Hz, 1H, Ar-
H),5.37(s,2H,CH2),4.61(s,2H,CH2),3.94(s,3H,CH3),2.56(s,3H,CH3)；13C NMR(100MHz,
CDCl3)δ196.3,165.8,153.5,149.7,145.3,137.0,129.7,128.7,127.3,121.1,121.0,
120.4,118.9,106.6,68.7,56.1,40.8,31.6。
Embodiment 3
8- acetyl group -5- methoxyl group -4- ((1- (3- nitrobenzophenone) -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo
The synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- nitrine -3- nitro
Catalyst Cu (CH is then added in benzene (0.6mmol, 0.0985g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 0.1984g, yield 93.7%.1H NMR
(400MHz,CDCl3) δ 8.58 (s, 1H, Ar-H), 8.28 (d, J=8.3Hz, 1H, Ar-H), 8.13 (d, J=8.8Hz, 1H,
), Ar-H 8.11 (s, 1H, CH), 7.72 (t, J=8.2Hz, 1H, Ar-H), 7.64 (d, J=8.9Hz, 1H, Ar-H), 6.73 (d,
J=9.0Hz, 1H, Ar-H), 5.36 (s, 2H, CH2),4.64(s,2H,CH2),3.96(s,3H,CH3),2.59(s,3H,CH3)
；13C NMR(100MHz,CDCl3)δ196.3,165.9,153.4,149.6,148.9,146.2,137.7,130.9,127.4,
125.7,123.1,121.2,121.1,118.9,115.2,106.6,68.7,56.1,41.0,31.5。
Embodiment 4
8- acetyl group -5- methoxyl group -4- ((1- (4- nitrobenzophenone) -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo
The synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -4- nitre
Catalysis Cu (CH is then added in base benzene (0.6mmol, 0.0984g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow particle shape solid 0.1835g, yield 86.7%.1H
NMR(400MHz,CDCl3) δ 8.39 (d, J=8.9Hz, 2H, Ar-H), 8.11 (s, 1H, CH), 7.95 (d, J=8.9Hz, 2H,
), Ar-H 7.64 (d, J=8.9Hz, 1H, Ar-H), 6.73 (d, J=9.0Hz, 1H, Ar-H), 5.36 (s, 2H, CH2),4.63
(s,2H,CH2),3.96(s,3H,CH3),2.58(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.3,166.0,
153.4,149.6,147.2,146.4,141.1,127.4,125.5,121.2,121.2,120.4,118.9,106.7,68.7,
56.1,41.0,31.5。
Embodiment 5
8- acetyl group -4- ((1- (2- hydroxy phenyl) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo
The synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 2- azido phenol of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water
Catalyst Cu (CH is then added in (0.6mmol, 0.081g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·H2O
(0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent, methylene chloride extraction, nothing to end of reaction
Aqueous sodium persulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains orange solid 0.1204g, yield 61.0%.1H NMR
(400MHz,CDCl3) δ 9.88 (s, 1H, OH), 8.09 (s, 1H, CH), 7.64 (d, J=8.9Hz, 1H, Ar-H), 7.36 (d, J
=8.1Hz, 1H, Ar-H), 7.29 (d, J=7.9Hz, 1H, Ar-H), 7.17 (d, J=8.2Hz, 1H, Ar-H), 6.97 (t, J=
7.7Hz, 1H, Ar-H), 6.72 (d, J=9.0Hz, 1H, Ar-H), 5.38 (s, 2H, CH2),4.64(s,2H,CH2),3.94(s,
3H,CH3),2.59(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.5,166.1,153.7,149.8,145.6,
144.6,133.9,130.8,130.4,127.9,127.5,125.7,124.1,121.2,118.9,106.7,68.8,56.2,
41.3,31.7。
Embodiment 6
8- acetyl group -4- ((1- (5- acetyl group -4- hydroxyl -2- methoxyphenyl) -1H-1,2,3- triazole-4-yl) first
Base) -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one synthesis
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 5- azido -2- hydroxyl
Catalysis is then added in base -4- methoxyacetophenone (0.6mmol, 0.1243g) and sodium ascorbate (0.1mmol, 19.81mg)
Agent Cu (CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction to end of reaction, is spin-dried for molten
Agent, methylene chloride extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains brick-red solid 0.1819g, yield
It is 78.0%.1H NMR(400MHz,CDCl3)δ12.83(s,1H,OH),8.01(s,1H,Ar-H),7.86(s,1H,CH),
7.61 (d, J=9.0Hz, 1H, Ar-H), 6.70 (d, J=9.0Hz, 1H, Ar-H), 6.55 (s, 1H, Ar-H), 5.44 (s, 2H,
CH2),4.61(s,2H,CH2),3.96(s,3H,CH3),3.84(s,3H,CH3),2.57(s,6H,CH3)；13C NMR
(100MHz,CDCl3)δ202.8,196.4,165.8,165.1,157.8,153.6,149.9,143.9,128.1,127.2,
124.9,121.1,118.7,118.7,113.2,106.6,100.8,68.7,56.5,56.1,40.3 31.5,26.5。
Embodiment 7
8- acetyl group -4- ((1- (2- (2- hydroxyl -4- methoxyphenyl) -2- oxoethyl) -1H-1,2,3- triazole -4-
Base) methyl) -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one synthesis
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 2- azido -1- (2-
Hydroxyl -4- methoxyphenyl) ethyl ketone (0.6mmol, 0.1243g) and sodium ascorbate (0.1mmol, 19.81mg), then it is added
Catalyst Cu (CH3COO)2·H2O (0.05mmol, 9.98mg), reacts at room temperature, TLC monitoring reaction.To end of reaction, rotation
Dry solvent, methylene chloride extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains white solid 0.1420g, receives
Rate 60.9%.,1H NMR(400MHz,CDCl3) δ 11.87 (s, 1H, OH), 7.61 (s, 1H, CH), 7.58 (d, J=4.6Hz,
2H, Ar-H), 6.67 (d, J=9.0Hz, 1H, Ar-H), 6.49 (dd, J=9.2,2.4Hz, 1H, Ar-H), 6.44 (d, J=
1.8Hz,1H,Ar-H),5.69(s,2H,CH2),5.36(s,2H,CH2),4.60(s,2H,CH2), 3.87 (d, J=16.1Hz,
6H,CH3),2.57(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.4,193.1,167.2,165.8,165.8,
153.6,149.8,144.9,130.3,127.2,124.5 121.0,118.9,111.2,108.9,106.6,101.3,68.7,
56.1,55.8,54.2,40.9,31.6.
Embodiment 8
8- acetyl group -4- ((1- (4- bromophenyl) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo
The synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -4- bromine
Catalyst Cu (CH is then added in benzene (0.6mmol, 0.1188g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 0.1369g, yield 59.9%.1H NMR
(400MHz,CDCl3) δ 7.96 (s, 1H, CH), 7.61 (q, J=8.9Hz, 5H, Ar-H), 6.71 (d, J=9.0Hz, 1H, Ar-
H),5.35(s,2H,CH2),4.61(s,2H,CH2),3.94(s,3H,CH3),2.57(s,3H,CH3)；13C NMR(100MHz,
CDCl3)δ196.3,165.9,153.5,149.7,145.6,136.0,132.9,127.3,122.3,121.8,121.1,
121.0,118.9,106.6,68.7,56.1,40.9,31.5。
Embodiment 9
8- acetyl group -5- methoxyl group -4- ((1- (2- methyl-5-nitrophenyl) -1H-1,2,3- triazole-4-yl) methyl) -
The synthesis of 2H- benzo [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 2- azido -1- first
Catalyst Cu is then added in base -4- nitrobenzene (0.6mmol, 0.1069g) and sodium ascorbate (0.1mmol, 19.81mg)
(CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains light yellow solid 0.1822g, and yield is
83.3%.1H NMR(400MHz,CDCl3) δ 8.25 (d, J=8.6Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 7.77 (s,
1H, CH), 7.63 (d, J=9.0Hz, 1H, Ar-H), 7.54 (d, J=8.4Hz, 1H, Ar-H), 6.71 (d, J=9.0Hz, 1H,
Ar-H),5.40(s,2H,CH2),4.62(s,2H,CH2),3.95(s,3H,CH3),2.58(s,3H,CH3),2.27(s,3H,
CH3).；13C NMR(100MHz,CDCl3)δ196.3,165.9,153.5,149.8,146.5,145.2,141.4,136.8,
132.5,127.4,124.3,124.3,121.2,121.2,118.9,106.6,68.7 56.1,40.9,31.5,18.5。
Embodiment 10
8- acetyl group -4- ((1- (2- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo
The synthesis of 3 (4H) -one of [b] [1,4] oxazines
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -2- fluorine
Catalyst Cu (CH is then added in benzene (0.6mmol, 0.0823g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow viscous liquid 0.1479g, yield 74.6%.1H NMR
(400MHz,CDCl3) δ 7.99 (s, 1H, CH), 7.90 (t, J=7.7Hz, 1H, Ar-H), 7.62 (d, J=9.0Hz, 1H, Ar-
), H 7.40 (q, J=7.3,6.8Hz, 1H, Ar-H), 7.31-7.23 (m, 2H, Ar-H), 6.70 (d, J=9.0Hz, 1H, Ar-
H),5.42(s,2H,CH2),4.62(s,2H,CH2),3.94(s,3H,CH3),2.58(s,3H,CH3)；13C NMR(100MHz,
CDCl3) δ 196.4,165.8,154.5,153.5,152.0,149.9,144.9,130.1 (d, J=7.7Hz), 127.3,
125.2 (d, J=3.7Hz), 124.8,124.0 (d, J=8.2Hz), 121.1,118.8,117.0 (d, J=19.8Hz),
106.6,68.7,56.1,40.6,31.6。
Embodiment 11
8- acetyl group -4- ((1- (the chloro- 2- nitrobenzophenone of 4-) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -
The synthesis of 2H- benzo [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -4- first
Catalyst Cu is then added in base -2- nitrobenzene (0.6mmol, 0.1191g) and sodium ascorbate (0.1mmol, 19.81mg)
(CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 96.2mg, yield 42.0%.1H
NMR(600MHz,CDCl3) δ 8.03 (s, 1H, CH), 7.73 (d, J=11.2Hz, 2H, Ar-H), 7.63 (d, J=8.8Hz, 1H,
), Ar-H 7.54 (d, J=8.3Hz, 1H, Ar-H), 6.70 (d, J=8.8Hz, 1H, Ar-H), 5.35 (s, 2H, CH2),4.62
(s,2H,CH2),3.89(s,3H,CH3),2.58(s,3H,CH3)；13C NMR(150MHz,CDCl3)δ196.4,166.0,
153.5,149.6,145.7,144.6,136.7,133.8,128.8,128.7,127.4,125.8,124.0,121.1,
118.8,106.6,68.7,56.1,41.2,31.5。
Embodiment 12
8- acetyl group -4- ((1- (the chloro- 2- nitrobenzophenone of 5-) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -
The synthesis of 2H- benzo [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 2- azido -4- of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water are chloro-
Catalyst Cu is then added in 1- nitrobenzene (0.6mmol, 0.1191g) and sodium ascorbate (0.1mmol, 19.81mg)
(CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 0.1700g, and yield is
73.96%.1H NMR(400MHz,CDCl3) δ 8.02 (d, J=8.7Hz, 1H, Ar-H), 7.75 (s, 1H, CH), 7.65-7.61
(m, 3H, Ar-H), 6.71 (d, J=9.0Hz, 1H, Ar-H), 5.35 (s, 2H, CH2),4.63(s,2H,CH2),3.89(s,3H,
CH3),2.59(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.4,166.0,153.5,149.6,145.8,142.5,
140.1,131.2,130.7,128.0,127.4,126.8,124.0,121.1,118.8,106.6,77.2,77.0,68.7,
56.1,41.2,31.6。
Embodiment 13
8- acetyl group -4- ((1- trimethylphenyl -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo [b]
[1,4] synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 2- azido -1,3 of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water,
Catalyst Cu is then added in 5- trimethylbenzene (0.6mmol, 0.0967g) and sodium ascorbate (0.1mmol, 19.81mg)
(CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 0.1150g, and yield is
54.7%.1H NMR(600MHz,CDCl3) δ 7.60 (d, J=8.9Hz, 1H, Ar-H), 7.36 (s, 1H, CH), 6.92 (s, 2H,
), Ar-H 6.64 (d, J=8.9Hz, 1H, Ar-H), 5.48 (s, 2H, CH2),4.61(s,2H,CH2),3.90(s,3H,CH3),
2.56(s,3H,CH3),2.31(s,3H,CH3),1.78(s,6H,CH3)；13C NMR(100MHz,CDCl3)δ196.2,165.8,
153.7,150.2,144.1,140.0,134.9,133.3,129.0,127.3,124.1,120.9,118.5,106.4,68.8,
56.1,40.6,31.6,21.1,17.0。
Embodiment 14
8- acetyl group -5- methoxyl group -4- ((the o- tolyl -1H-1,2,3- triazole-4-yl of 1-) methyl) -2H- benzo [b]
[1,4] synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -2- first
Catalyst Cu (CH is then added in base benzene (0.6mmol, 0.0799g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction.To end of reaction, it is spin-dried for solvent, methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow viscous liquid 0.1747g, yield 89.1%.1H NMR
(400MHz,CDCl3) δ 7.64-7.62 (m, 2H, CH, Ar-H), 7.38 (dd, J=6.3,1.8Hz, 1H, Ar-H), 7.33-
7.26 (m, 3H, Ar-H), 6.69 (d, J=9.0Hz, 1H, Ar-H), 5.44 (s, 2H, CH2),4.62(s,2H,CH2),3.94(s,
3H,CH3),2.58(s,3H,CH3),2.08(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.3,165.8,153.6,
149.9,144.3,136.4,133.6,131.4,129.8,127.3,126.8,125.9,124.2,121.1,118.8,
106.6,68.7,56.1,40.8,31.6,17.7。
Embodiment 15
8- acetyl group -4- ((1- (2,6- diisopropyl) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzene
And the synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 2- azido -1,3- of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water
Catalyst Cu is then added in diisopropyl benzene (0.6mmol, 0.1219g) and sodium ascorbate (0.1mmol, 19.81mg)
(CH3COO)2·H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains pink solid 0.1673g, and yield is
72.3%.1H NMR(600MHz,CDCl3) δ 7.62 (d, J=8.8Hz, 1H, Ar-H), 7.43 (t, J=7.5Hz, 1H, Ar-H),
7.37 (s, 1H, CH), 7.21 (d, J=7.6Hz, 2H, Ar-H), 6.64 (d, J=8.8Hz, 1H, Ar-H), 5.55 (s, 2H,
CH2),4.61(s,2H,CH2),3.92(s,3H,CH3),2.55(s,3H,CH3), 1.00 (dd, J=34.6,6.5Hz, 12H,
CH3)；13C NMR(150MHz,CDCl3)δ196.0,165.8,153.7,150.3,145.9,143.8,133.1,130.8,
127.4,125.0,123.7,120.83,118.2,106.4,68.8,56.1,40.1,31.6,28.3,24.1,23.8。
Embodiment 16
8- acetyl group -5- methoxyl group -4- ((1- (naphthalene -1- base) -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo [b]
[1,4] synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
The mixed solution, 1- nitrine naphthalene of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water
Catalyst Cu (CH is then added in (0.6mmol, 0.1015g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·H2O
(0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent, methylene chloride extraction, nothing to end of reaction
Aqueous sodium persulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains brown viscous liquid 0.1849g, yield 86.3%.1H NMR
(600MHz,CDCl3) δ 7.99 (d, J=7.1Hz, 1H, Ar-H), 7.93 (d, J=8.1Hz, 1H, Ar-H), 7.81 (s, 1H,
), CH 7.67 (d, J=8.9Hz, 1H, Ar-H), 7.55 (dd, J=11.5,6.8Hz, 3H, Ar-H), 7.46 (t, J=7.5Hz,
1H, Ar-H), 7.31 (d, J=8.4Hz, 1H, Ar-H), 6.73 (d, J=8.9Hz, 1H, Ar-H), 5.51 (s, 2H, CH2),
4.63(s,2H,CH2),3.97(s,3H,CH3),2.58(s,3H,CH3)；13C NMR(150MHz,CDCl3)δ196.3,165.9,
153.6,150.0,144.4,134.1,133.6,130.4,128.4,128.3,127.9,127.3,127.1,125.4,
125.0,123.5,122.0,121.1,118.7,106.6,68.8,56.2,40.7,31.6。
Embodiment 17
8- acetyl group -4- ((1- benzyl -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo [b] [1,4]
The synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
Mixed solution, (azido-methyl) benzene of [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the 2mL tert-butyl alcohol and water
Catalyst Cu (CH is then added in (0.6mmol, 0.0799g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·H2O
(0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction to end of reaction, is spin-dried for solvent, methylene chloride
Extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow viscous liquid 0.1678g, yield 85.6%.1H NMR(600MHz,CDCl3) δ 7.58 (d, J=8.9Hz, 1H, Ar-H), 7.32 (d, J=11.7Hz, 4H, Ar-H), 7.13
(s, 2H, CH, Ar-H), 6.62 (d, J=8.9Hz, 1H, Ar-H), 5.42 (s, 2H, CH2),5.30(s,2H,CH2),4.55(s,
2H,CH2),3.85(s,3H,CH3),2.54(s,3H,CH3)；13C NMR(150MHz,CDCl3)δ196.3,165.7,153.5,
144.8,134.7,129.1,128.7,127.8,127.2,122.5,120.9,118.7,106.5,77.0,68.7,56.0,
54.1,40.6,31.6。
Embodiment 18
8- acetyl group -4- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -5- methoxyl group -2H- benzo
The synthesis of [b] [1,4] oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -4- fluorine
Catalyst Cu (CH is then added in benzene (0.6mmol, 0.0822g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), in room temperature reaction, TLC monitoring reaction is spin-dried for solvent to end of reaction, and methylene chloride extracts,
Anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow powdery solid 0.1703g, yield 85.9%.1H
NMR(400MHz,CDCl3) δ 7.91 (s, 1H, CH), 7.69-7.59 (m, 3H, Ar-H), 7.18 (t, J=8.4Hz, 2H, Ar-
), H 6.70 (d, J=9.0Hz, 1H, Ar-H), 5.35 (s, 2H, CH2),4.61(s,2H,CH2),3.94(s,3H,CH3),2.57
(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ196.4,165.9,163.6,161.1,153.5,149.7,145.5,
133.3,127.4,122.4 (d, J=8.6Hz), 121.3,121.1,118.9,116.8,116.6,106.7,68.7,56.1,
40.9,31.6。
Embodiment 19
8- acetyl group -5- methoxyl group -4- ((1- p-methylphenyl -1H-1,2,3- triazole-4-yl) methyl) -2H- benzo [b]
[1,4] synthesis of oxazines -3 (4H) -one
In the stand up reaction bottle of 25mL, 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo is sequentially added
[b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one (0.5mmol, 0.1295g), the mixed solution of the 2mL tert-butyl alcohol and water, 1- azido -4- first
Catalyst Cu (CH is then added in base benzene (0.6mmol, 0.0799g) and sodium ascorbate (0.1mmol, 19.81mg)3COO)2·
H2O (0.05mmol, 9.98mg), reacts at room temperature, TLC monitoring reaction, to end of reaction, is spin-dried for solvent, methylene chloride extraction
It takes, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains yellow solid 0.1694g, yield 86.3%.1H NMR
(400MHz,CDCl3) δ 7.90 (s, 1H, CH), 7.61 (d, J=9.0Hz, 1H, Ar-H), 7.55 (d, J=8.3Hz, 2H, Ar-
), H 7.27 (d, J=8.2Hz, 2H, Ar-H), 6.70 (d, J=9.0Hz, 1H, Ar-H), 5.37 (s, 2H, CH2),4.61(s,
2H,CH2),3.94(s,3H,CH3),2.57(s,3H,CH3),2.39(s,3H,CH3)；13C NMR(100MHz,CDCl3)δ
196.3,165.8,153.6,149.8,145.1,138.8,134.7,130.2,127.3,121.1,121.0,120.3,
118.9,106.6,68.7,56.1,40.9,31.5,21.1。
Embodiment 20
Anti-tumor activity test to Non-small cell lung carcinoma cell and human cervical carcinoma cell
(1) cell recovery
Before recovery cell, we first from ATCC official's online enquiries recovery cell institute culture medium to be used, are then taken
Prepared culture medium (5mL) and fetal calf serum (1mL) are added into 50mL culture bottle, get 37 DEG C or so of warm water ready, then
Quickly the cell to be recovered is removed from liquid nitrogen, is placed in a beaker and rocks promotion dissolution, reach mixture of ice and water shape to it
State quickly removes, and frozen stock solution is added in aseptic operating platform and shifts to an earlier date in ready culture bottle, is put into 37 DEG C, volume point
Number is 5%CO2It is cultivated in incubator, next day cleans and changes to new culture medium.
(2) cell passes on
After cell recovery, when cells being waited to be grown in covering to about 80% bottom of bottle in culture bottle, cell passage is carried out.First from
The culture bottle for needing to carry out cell passage is taken out in incubator, the old culture medium abandoned in culture bottle is inhaled, with PBS (50mL culture bottle
2mL is added every time, 4mL is added in 125mL culture bottle every time) cleaning 2 times, trypsase (the 50mL training of 0.15wt% is then added
Support bottle and 1mL be added, 2mL is added in 125mL culture bottle), it is put into incubator and digests about 40s, observed with inverted microscope, etc.
When cell is largely dispersed into spherical shape, culture medium (2mL or 4mL) can be added and terminate digestion, blown and beaten down with Dispette
Carry out bottom of bottle cell, and cell suspending liquid is transferred in sterilized centrifuge tube, is centrifuged 5min with centrifuge 1000rpm, abandons
Supernatant is removed, is mixed after 1mL culture medium is added, takes a certain amount of cell suspension point to carry out into new culture bottle according to cell density
Culture.
(3) target compound tests the anti-tumor activity of cancer cell
Using the MTT method (MTT) of standard, the activity that target compound inhibits tumor cell proliferation is measured.It takes pair
Number phase cell, after cleaning 2 times with PBS, is got off cell dissociation with the trypsase of 0.15wt%, is added culture medium termination and is disappeared
Change, cell suspending liquid is transferred in sterile centrifugation tube, is centrifuged 5min with centrifuge 1000rpm.Liquid is discarded supernatant, is added certain
The culture medium of amount is observed under inverted microscope and carries out cell count.A certain amount of culture medium is added according to count results to match
It is made 5 × 104The single cell suspension of cells/mL, is inoculated in 96 orifice plates, every 100 μ L of hole, overnight incubation, and next day uses difference respectively
The complete culture solution that the compound to be screened of concentration is prepared handles cell, while isometric solvent control group.Each set 3 again
Hole, respectively at 37 DEG C, volume fraction 5%CO2After cultivating 72h respectively, 20 μm of 5mg/mL MTT solution is added in every hole, continues to cultivate
4h, abandon supernatant, then plus 150 μ L of DMSO, with microplate reader (562nm) measurement absorbance (A) value (A value and viable count are at just
Than), take its average value.
Anti-tumor activity of 1 compound of table to NCI-H1299 cell and HeLa cell
For 1 compound of table to the anti-tumor activity test result of NCI-H1299 cell and HeLa cell, number 19 is positive right
According to a group experiment.
Embodiment above describes basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (5)
1. Paeonol with anti-tumor activity and benzoxazine compounds, it is characterised in that its structural formula are as follows:Wherein R is phenyl, substituted-phenyl or naphthalene, taking on the substituted-phenyl phenyl ring
Dai Jiwei halogen atom, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl-carbonyl, nitro or hydroxyl, n be between 0~4 any one is whole
Number.
2. the preparation method of a kind of Paeonol with anti-tumor activity described in claim 1 and benzoxazine compounds,
It is characterized in that specific steps are as follows:
The synthesis of step S1:1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone
Paeonol and the concentrated sulfuric acid are placed in reaction vessel, in -15 DEG C of dropwise addition concentrated nitric acids, are made after being added dropwise in room temperature reaction
Product 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone；
The synthesis of step S2:1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone
1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone and glacial acetic acid are placed in reaction vessel, in ice after its dissolution
Zinc powder is added under water bath condition, reaction is stirred at room temperature, product 1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone is made；
The synthesis of step S3:8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one
8- acetyl group -5- methoxyl group -2H- benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one and dichloroethanes are placed in reaction vessel,
In 0 DEG C of addition chloracetyl chloride, TLC monitors it and is spin-dried for solvent after completion of the reaction, DMF and Anhydrous potassium carbonate is added, in room temperature reaction
Product 8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one is made；
The synthesis of step S4:8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
By 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one, 3- propargyl bromide,
Anhydrous potassium carbonate and DMF are placed in reaction vessel, and product 8- acetyl group -5- methoxyl group -4- (propyl- 2- alkynes is made in reacting at room temperature
Base) -2H- benzo [b] [1,4] oxazines -3 (4H) -one；
Step S5: the synthesis of Paeonol and benzoxazine compounds
8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 is sequentially added in the reactor
(4H) -one, the mixed solution of the tert-butyl alcohol and water, azidomethyl phenyl nitrogen compound and sodium ascorbate, add catalyst Cu
(CH3COO)2·H2Target product Paeonol and benzoxazine compounds are made in reacting at room temperature in O.
3. the preparation method of Paeonol with anti-tumor activity according to claim 2 and benzoxazine compounds,
It is characterized in that specific steps are as follows:
The synthesis of step S1:1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone
120mmol Paeonol and the 100mL concentrated sulfuric acid are placed in the reaction flask of 500mL, in -15 DEG C of dropwise addition 5.4mL concentrated nitric acids, drop
In room temperature reaction after adding, to end of reaction, reaction solution is poured into 500mL ice water, is filtered for TLC monitoring reaction, drying filter
Cake, column chromatographic purifying obtain yellow solid 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone 5.91g, yield 23%；
The synthesis of step S2:1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone
25mmol 1- (2- hydroxyl -4- methoxyl group -3- nitrobenzophenone) ethyl ketone and 25mL glacial acetic acid are placed in the reaction flask of 100mL
In, 0.25mol zinc powder is added in ice-water bath after its dissolution, is stirred at room temperature reaction, TLC monitoring is reacted, to end of reaction,
Neutralization reaction, ethyl acetate extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains ginger-colored particulate powder
Solid 1- (3- amino -2- hydroxyl -4- methoxyphenyl) ethyl ketone 2.62g, yield 58%；
The synthesis of step S3:8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] oxazines -3 (4H) -one
15mmol 8- acetyl group -5- methoxyl group -2H- benzo [b] [1,4] (4H) -one of oxazines -3 and 40mL dichloroethanes are placed in
In the reaction flask of 100mL, in 0 DEG C of addition 16.5mmol chloracetyl chloride, TLC monitors it and is spin-dried for solvent after completion of the reaction, is added
30mL DMF and 18mmol Anhydrous potassium carbonate wash DMF three times, dichloro to end of reaction in room temperature reaction, TLC monitoring reaction
Methane extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains white solid 8- acetyl group -5- methoxyl group -2H-
Benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one 2.84g, yield 86%；
The synthesis of step S4:8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one
By 10mmol 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [1,4] oxazines -3 (4H) -one,
12mmol 3- propargyl bromide, 12mmol Anhydrous potassium carbonate and 20mL DMF are placed in 100mL reaction flask in room temperature reaction, TLC monitoring
Reaction washes DMF three times to end of reaction, and ethyl acetate extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains
To white solid 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzo [b] [Isosorbide-5-Nitrae] oxazines -3 (4H) -one 2.51g,
Yield is 97%；
Step S5: the synthesis of Paeonol and benzoxazine compounds
0.5mmol 8- acetyl group -5- methoxyl group -4- (Propargyl) -2H- benzene is sequentially added in the stand up reaction bottle of 25mL
And [b] [1,4] oxazines -3 (4H) -one, the mixed solution of the 2mL tert-butyl alcohol and water, 0.6mmol azidomethyl phenyl nitrogen compound and
Then 0.05mmol catalyst Cu (CH is added in 0.1mmol sodium ascorbate3COO)2·H2O, in room temperature reaction, TLC monitoring is anti-
It answers, to end of reaction, is spin-dried for solvent, methylene chloride extraction, anhydrous sodium sulfate is dry, and suction filtration is spin-dried for, and column chromatographic purifying obtains mesh
Mark product Paeonol and benzoxazine compounds.
4. the preparation side of Paeonol with anti-tumor activity according to claim 2 or 3 and benzoxazine compounds
Method, it is characterised in that: the volume ratio of the tert-butyl alcohol and water is 1:1 in the mixed solution of the tert-butyl alcohol described in step S5 and water.
5. simultaneously benzoxazine compounds are being prepared for inhibiting people Paeonol with anti-tumor activity described in claim 1
Application in the growth of non-small cell lung cancer cell NCI-H1299 cell or/and HeLa Cells growth drug.
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| CN110437156A (en) * | 2019-08-26 | 2019-11-12 | 桂林医学院 | Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application |
| CN114288279A (en) * | 2021-12-27 | 2022-04-08 | 浙江百越生物技术有限公司 | New application of paeonol in preparation of anti-lung cancer drugs |
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| CN114288279A (en) * | 2021-12-27 | 2022-04-08 | 浙江百越生物技术有限公司 | New application of paeonol in preparation of anti-lung cancer drugs |
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