CN106045980B - A kind of quinazoline derivant and preparation method thereof - Google Patents
A kind of quinazoline derivant and preparation method thereof Download PDFInfo
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- CN106045980B CN106045980B CN201610394617.5A CN201610394617A CN106045980B CN 106045980 B CN106045980 B CN 106045980B CN 201610394617 A CN201610394617 A CN 201610394617A CN 106045980 B CN106045980 B CN 106045980B
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- 0 *c1c[n]nn1 Chemical compound *c1c[n]nn1 0.000 description 1
- SLKOSJBZJJZHIN-UHFFFAOYSA-N COc(cc(c(C1)c2)N=CN=C1Nc(cc1Cl)ccc1F)c2O Chemical compound COc(cc(c(C1)c2)N=CN=C1Nc(cc1Cl)ccc1F)c2O SLKOSJBZJJZHIN-UHFFFAOYSA-N 0.000 description 1
- YNULYJVKQWEOIY-UHFFFAOYSA-N COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCN Chemical compound COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCN YNULYJVKQWEOIY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a kind of quinazoline derivant and preparation method, by the methoxyquinazoline hydrochloride of 46 ammonia ethyoxyl of (3 amino) phenyl 7 and 1,2, the aldehyde of 3 triazole 4 is added in reactor, reaction dissolvent and catalyst are added, after stirring, in 80 120 DEG C of reactions；After completion of the reaction, product is cooled to after room temperature, and vacuum distillation removes solvent, and gained solid ethyl alcohol recrystallization is dried in vacuo to obtain off-white powder.A kind of quinazoline derivant that the present invention is provided organically combines quinazoline, schiff bases and triazole group, with certain antitumor action, additionally aids the drug-fast possibility that reduction tumour cell is produced to medicine.The synthetic route have the advantages that raw material be easy to get, it is simple to operate, save solvent, reduce pollution, it is easy to industrialized production.
Description
Technical field
The invention belongs to medicine and intermediate synthesis technical field, and in particular to a kind of quinazoline derivant and preparation side
Method.
Background technology
Quinazoline compounds are the nitrogen-containing heterocycle compounds that a class has good biological activity, and it is in antibacterial, anti-inflammatory, anti-
Excellent activity is all shown in terms of hypertension and anticancer.Find that 4- anilinoquinazolines can be used as from Fry in 1994 etc.
Since the specific inhibitor of EGFR EGFR-TKs, quinazoline compounds turn into tyrosine kinase inhibitor class antineoplastic
One of focus of research and development.There is document report to claim 4- anilinoquinazoline class compounds to be active highest, the choosing found so far
The best class tyrosine kinase inhibitor of selecting property.Wherein, 4- substituted anilines quinazoline compounds are quinazoline ditosylate salt tyrosine
The higher class compound of activity in kinase inhibitor, wherein in numerous reports, finds main modification quinazoline 6 or 7
Position, obtained compound effect preferably, is all shown anti-well to kinds of tumors such as breast cancer, lung cancer, stomach cancer, prostate cancer
Function of tumor.Four small-molecule drug listings associated therewith are had at present.First generation EGFR inhibitor Gefitinib
(Gefitinib) and Erlotinib (Erlotinib) oneself through by food and medicine Surveillance Authority of the U.S. approval treatment non-small cell
Lung cancer patient.Lapatinib (Lapatinib) as a kind of bidirectional reversible EGFR and HER-2 inhibitor oneself through go through use
In the treatment of breast cancer.ZD6474 (Vandetanib) is used to treat advanced NSCLC.And in the small-molecule drug of 4 listings
All contain identical 4- anilinoquinazoline mother nucleus structures.
3-triazole compounds are the very important compounds of a class, and stability and good biology with aromatic rings are simultaneous
Capacitive, the pharmacophore of different substrates is connected into as a molecule by triazole loop chain, and its product can pass through hydrogen bond and dipole is made
For improving the binding ability with biological targets, existing numerous triazole derivatives are used as antibacterial, antitumor, anti-inflammatory, anti-
The medicines such as hypertension are widely used in clinic.Schiff bases functional group, is also extremely valuable pharmacophoric group.Based on pharmacophore coupling
Strategy, to develop the antineoplastic of high-efficiency low-toxicity, 4- benzene is introduced by triazole and schiff bases bioactivity combination fragment respectively
In amido quinazoline structure unit, the new 4- anilinoquinazoline Schiff bases compounds containing triazole are synthesized, in medicine
Aspect has a wide range of applications.
The content of the invention
Present invention aims at provide a kind of quinazoline derivant and preparation method.
A kind of quinazoline derivant that the present invention is provided, its general structure is as follows：
The present invention also proposes a kind of preparation method of quinazoline derivant, with 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethoxies
Base -7- methoxyquinazoline hydrochlorides are raw material, and 1,2,3- tri- nitrogen -4- aldehyde azoles occur nucleophilic addition and are made.Its synthetic route is：
Comprise the following steps that：
4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides are added into dry reactor, plus
Enter reaction dissolvent and catalyst, after stirring, in 80-120 DEG C of reaction.After completion of the reaction, product is cooled to after room temperature, decompression
Solvent is distilled off, gained solid ethyl alcohol recrystallization is dried in vacuo to obtain off-white powder.Wherein：4- (the chloro- 4- fluorine of 3-) phenylamino
The mol ratio of base -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides and 1,2,3- triazole -4- aldehyde is 1：1~1.5；4- (the chloro- 4- of 3-
Fluorine) mol ratio of phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides and catalyst is 1：0.1~0.2；Reaction dissolvent is second
The arbitrarily mixing of alcohol, isopropanol, toluene, N, N-any of dimethylformamide or dimethyl sulfoxide or above solvent is molten
Agent, preferably toluene；Catalyst is formic acid, acetic acid, benzene sulfonic acid, tri-chlorination caesium, any of titanium tetrachloride, preferably four chlorinations
Titanium.
Present invention also offers application of the quinazoline derivant in antineoplastic is prepared.
A kind of quinazoline derivant that the present invention is provided, quinazoline, schiff bases and triazole group are organically combined, tool
There is certain antitumor action, can be as kinases inhibitor, and available for the coordination with the metal such as metal platinum, ruthenium, formed
Metal complex, particularly significant application prospect is suffered from biomedical, medicine and other fields, additionally aids reduction tumour cell pair
The drug-fast possibility that medicine is produced.There is the synthetic route raw material to be easy to get, it is simple to operate, save solvent, to reduce pollution etc. excellent
Point, it is easy to industrialized production.
Embodiment
It is following that the present invention is further illustrated by embodiment, but present disclosure can not be limited.
Embodiment 1：The preparation of 4- (3- amino) phenyl -6- hydroxyl -7- methoxyquinazoline hydrochlorides
(1) preparation of (the 3H)-quinazolinone (2) of 6- hydroxyls -7- methoxyl groups -4
2- amino -5- hydroxyl -4- methoxy ethylbenzoates (4.9g, 25mmol) are added into reactor, 30mL is added
Formyl amine solvent, adds ammonium formate, is warming up to 170 DEG C and reacts 12 hours.After the completion of reaction, room temperature is first cooled to, ice is then used
Water-bath is cooled to solid precipitation, and filtering, gained solid obtains (the 3H)-quinazolinone of 6- hydroxyl -7- methoxyl groups -4 with recrystallizing methanol
4.3g, yield 89.6%.
(2) preparation of (the 3H)-quinazolinone (3) of 6- ethoxycarbonyies -7- methoxyl groups -4
(the 3H)-quinazolinone (4.8g, 25mmol) of 6- hydroxyl -7- methoxyl groups -4 is added into reactor, 20mL second is added
Acid anhydrides, adds pyridine (3.95g, 50mmol), is warming up to 100 DEG C and reacts 2 hours.After the completion of reaction, room temperature is first cooled to, is rotated
Evaporated solvent, adds water into residue, separates out solid, and gained solid is washed with water, and filters, and dry 6- ethoxycarbonyies-
7- methoxyl groups -4 (3H)-quinazolinone 2.26g, yield 96.6%.
(3) preparation of the chloro- 6- ethoxycarbonyies -7- methoxyl groups -4 (3H) of 4--quinazoline (4)
(the 3H)-quinazolinone (5g, 21.4mmol) of 6- ethoxycarbonyl -7- methoxyl groups -4 is added into reactor, 30mL is added
Thionyl chloride, adds 0.5mL DMFs, is warming up to back flow reaction 2 hours.After the completion of reaction, rotary evaporation goes out
Go to add saturated sodium bicarbonate solution under thionyl chloride, ice-water bath into residue, stirring is released to without gas.Add dichloromethane
Alkane is extracted, anhydrous sodium sulfate drying.Drier is filtered to remove, rotary evaporation removes solvent and obtains the chloro- 6- ethyl esters of faint yellow solid 4-
(the 3H)-quinazoline 5.23g of base -7- methoxyl groups -4, yield 86.1%.
(4) preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ethoxycarbonyl -7- methoxyquinazoline hydrochlorides (5)
The chloro- 6- ethoxycarbonyies -7- methoxyl groups -4 (3H) of 4--quinazoline (2.52g, 10mmol) is added into reactor, is added
50mL isopropanols dissolve, and add m-phenylene diamine (MPD) (1.6g, 11mmol), after stirring, and are warming up to backflow, react 2 hours.Reaction
After the completion of, it is cooled to room temperature.Filtering, gained solid obtains 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ethoxycarbonyies -7- with ethyl alcohol recrystallization
Methoxyquinazoline hydrochloride 3.34g, yield 92.5%.
(5) preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -6- hydroxyl -7- methoxyquinazoline hydrochlorides (6)
Added into reactor 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ethoxycarbonyl -7- methoxyquinazoline hydrochlorides (3.61g,
10mmol), the dissolving of 30mL methanol is added, sodium methoxide (2.7g, 50mmol) is added, after stirring, backflow, reaction 3 is warming up to
Hour.After the completion of reaction, solid is filtered to remove, cooling crystallization obtains solid 4- (the chloro- 4- fluorine of 3-) phenylamino -6- hydroxyl -7- methoxies
Base quinazoline 3.04g, yield 95.3%.
(6) preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides (7)
Added into reactor 4- (the chloro- 4- fluorine of 3-) phenylamino -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3.19g,
10mmol), 30mL DMFs are added and makees solvent, add potassium carbonate (2.07g, 15mmol) and 2-chloroethyl amine
(1.2g, 15mmol), is heated to backflow, reacts 5 hours.After reaction terminates, solid is filtered to remove, filtrate rotary evaporation removes molten
Agent.60mL water is added into residue, solid is separated out, filtering, gained solid recrystallizes to obtain 4- (the chloro- 4- fluorine of 3-) with ethanol/water
Phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochloride 3.1g, yield 85.5%.1H NMR(DMSO-d6,300MHz):9.04(s,
1H),8.56(s,1H),8.26(m,1H),7.79(m,1H),7.72(s,1H),7.31(t,1H),7.24(s,1H),4.32(t,
2H),3.99(s,3H),3.67(t,2H).MS(ESI):m/z 363(M+H)；Anal.Calcd.for C17H15ClFN4O2:C,
56.28；H,4.45；N,15.44；found:C,56.08；H,4.43；N,15.38.
Embodiment 2：The preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -7- methoxyquinazoline hydrochlorides schiff bases (1)
Added into reactor 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides (1.81g,
5mmol), 1,2,3- triazole -4- aldehyde (0.49,5mmol), add 30mL toluene and make solvent, add titanium tetrachloride (0.095g,
0.5mmol), after stirring, backflow is warming up to, is reacted 2 hours.After the completion of reaction, rotary evaporation removes toluene, and residue is used
Ethyl alcohol recrystallization or silica gel column chromatography obtain 1,2,3- triazole -4- anilinoquinazoline schiff bases 1.84g, yield 83.5%.1H NMR(DMSO-d6,300MHz):8.50(s,1H),8.32(s,1H),8.28(s,1H),8.14(s,1H),7.85(s,1H),
7.81(s,1H),7.45(m,1H),7.21(s,1H),4.16(t,2H),4.02(s,3H),3.82(t,2H).MS(ESI):m/z
442(M+H)；Anal.Calcd.for C20H17ClFN7O2:C,54.37；H,3.88；N,22.19；Found:C,54.64；H,
3.79；N,22.21.
Embodiment 3：The preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -7- methoxyquinazoline hydrochlorides schiff bases (1)
Added into reactor 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides (1.81g,
5mmol), 1,2,3- triazole -4- aldehyde (0.97,10mmol), addition 30mL ethanol as solvent, addition acetic acid (0.06g,
1mmol), after stirring, backflow is warming up to, is reacted 4 hours.After the completion of reaction, rotary evaporation removes solvent, residue second
Alcohol is recrystallized or silica gel column chromatography obtains 1,2,3- triazole -4- anilinoquinazoline schiff bases 1.62g, yield 73.5%.
Embodiment 4：The preparation of 4- (the chloro- 4- fluorine of 3-) phenylamino -7- methoxyquinazoline hydrochlorides schiff bases (1)
Added into reactor 4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides (1.81g,
5mmol), 1,2,3- triazole -4- aldehyde (0.49,5mmol), add 30mL N, and N-dimethylformamide makees solvent, adds trichlorine
Change caesium (0.168,1mmol), after stirring, be warming up to backflow, react 2 hours.After the completion of reaction, rotary evaporation removes molten
Agent, residue obtains 1,2,3- triazole -4- anilinoquinazoline schiff bases 1.91g with ethyl alcohol recrystallization or silica gel column chromatography,
Yield 86.8%.
Embodiment 5：Antitumor activity is tested
For the biological activity of compound, with human breast cancer cell (MCF-7) for research object, determine swollen with mtt assay
The proliferative conditions of oncocyte.
Specific implementation is as follows：Take the logarithm growth period tumour cell count, culture medium dilution after be inoculated in 96 well culture plates
Interior, per hole 100L cell liquid, concentration is about 3~5 × 104Individual/mL.Incubated overnight (5%CO2, 37 DEG C), treat that cell attachment is laggard
Row administration, sets administration group, positive controls and negative control group respectively.Complex to be measured is molten with the glucose of DMSO or 5%
Liquid is configured to reservoir, and before use with cell culture medium into 7 concentration gradients, wherein DMSO final concentration is no more than 4 ‰.Often
Individual concentration sets 5 multiple holes.Cultivated 24~48 hours after dosing, plus the MTT that 10L concentration is 5mg/mL, 37 DEG C are incubated 4 hours, go
Supernatant, 150L DMSO dissolvings are added per hole, are shaked.Determined with ELIASA under 570nm wavelength per hole OD values, and calculate suppression
Rate, does concentration-inhibiting rate curve and calculates IC50Value.
Quinazoline derivant made from embodiment 2-4 suppresses dense to the half of human breast cancer cell (MCF-7) test experiments
Spend IC50, and control group positive drug Cisplatin, Gefitinib are to human breast cancer cell (MCF-7) test result such as institute of table 1
Show.By experiment we have found that the quinazoline schiff base compounds of the triazole containing 1,2,3- of synthesis, which have, suppresses MCF-7 (human milks
Adenocarcinoma cell) tumour cell function, it is found that such compound is approached for inhibitory action and the Gefitinib of tumour cell, can
To find out that the quinazoline schiff base compounds containing 1,2,3- triazoles that we design have suppression function, tool in anti-tumor aspect
There is certain application prospect.
The human breast cancer cell of table -1 (MCF-7) test result
It is described above, only it is presently preferred embodiments of the present invention, any formal limitation not is made to the present invention, it is any ripe
Professional and technical personnel is known, it is without departing from the scope of the present invention, real to more than according to the technical spirit of the present invention
Apply any simple modification, equivalent substitution that example made and improve etc., still fall within technical solution of the present invention protection domain it
It is interior.
Claims (5)
1. a kind of quinazoline derivant, it is characterised in that its structural formula is as follows：
2. the preparation method of the quinazoline derivant described in claim 1, it is characterised in that synthetic route is：
Comprise the following steps that：
4- (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides and 1,2,3- triazole -4- aldehyde are added to
In reactor, reaction dissolvent and catalyst are added, after stirring, in 80-120 DEG C of reaction；After completion of the reaction, product is cooled to
After room temperature, vacuum distillation removes solvent, and gained solid ethyl alcohol recrystallization is dried in vacuo to obtain off-white powder；Wherein, the 4-
The mol ratio of (the chloro- 4- fluorine of 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides and 1,2,3- triazole -4- aldehyde is 1：1~
1.5；The mol ratio of 4- (the chloro- 4- fluorine of the 3-) phenylamino -6- ammonia ethyoxyl -7- methoxyquinazoline hydrochlorides and catalyst is 1：0.1
~0.2.
3. the preparation method of quinazoline derivant as claimed in claim 2, it is characterised in that：Reaction dissolvent is in the step
The arbitrarily mixing of ethanol, isopropanol, toluene, N, N-any of dimethylformamide or dimethyl sulfoxide or above solvent is molten
Agent.
4. the preparation method of quinazoline derivant as claimed in claim 2, it is characterised in that：Catalyst is first in the step
Any of acid, acetic acid, methanesulfonic acid, alchlor or titanium tetrachloride.
5. application of the quinazoline derivant described in claim 1 in antineoplastic is prepared.
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| CN107417735A (en) * | 2017-07-21 | 2017-12-01 | 浙江农林大学 | New E GFR and DNA double target spot ruthenium class anti-tumor complex a kind of molecular design method |
| CN109232539B (en) * | 2018-10-14 | 2021-01-26 | 上海耀大生物科技有限公司 | Bis-quinazoline Schiff base derivatives with anticancer activity and preparation and medical application thereof |
| CN109942499B (en) * | 2019-03-29 | 2022-03-22 | 湖南中医药大学 | Quinazoline derivative and preparation method and application thereof |
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|---|---|---|---|---|
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| CN1882580A (en) * | 2003-09-25 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as antiproliferative agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| CN1882580A (en) * | 2003-09-25 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as antiproliferative agents |
Non-Patent Citations (1)
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| Gefitinib analogue v1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa;Bao Zhang等;《PLoS One》;20121231;第7卷(第11期);e48748 1-10 * |
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