CN108191756A - A kind of quinoline and its preparation method and application - Google Patents
A kind of quinoline and its preparation method and application Download PDFInfo
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- CN108191756A CN108191756A CN201711316481.7A CN201711316481A CN108191756A CN 108191756 A CN108191756 A CN 108191756A CN 201711316481 A CN201711316481 A CN 201711316481A CN 108191756 A CN108191756 A CN 108191756A
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- quinoline
- reaction
- organic solvent
- breast cancer
- decyloxy
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- CNQOOEVGHXHNPR-UHFFFAOYSA-N CC(C)(CCc1cccc2c1nc(C)cc2C(OC)=O)OC Chemical compound CC(C)(CCc1cccc2c1nc(C)cc2C(OC)=O)OC CNQOOEVGHXHNPR-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to quinoline heterocyclic compound technical fields, more particularly to a kind of quinoline and its preparation method and application, the described quinoline is 6 decyloxy, 7 ethoxyquinoline, 3 carboxylic acid, ethyl ester or its hydrate, prodrug and pharmaceutically acceptable salt, structural formula are：And improve preparation method, using and the quinoline configuration pharmaceutical composition.Quinoline provided by the invention has higher medical value, for handling, treating or mitigate metastatic breast cancer and postclimacteric women advanced breast cancer.
Description
Technical field
The invention belongs to quinoline heterocyclic compound technical fields, and in particular to a kind of quinoline and preparation method thereof and
Using.
Background technology
Breast cancer belongs to malignant tumour common in women, and there are about 1,200,000 women every year in the whole world to suffer from breast cancer, and about 500,000
People dies of the disease.In the U.S., the probability that women suffers from breast cancer in all one's life is up to 1/8th, is the pernicious swollen of the death rate second
Knurl.The incidence of China's breast cancer rises year by year, and the metropolis incidence such as Beijing, Shanghai has become woman up to 56/,100,000
The malignant tumour of female's incidence first.
At present, it is still the critical issue for treating breast cancer to find a kind of efficient, stable, low side effect drug.Therefore, into
One step researches and develops novel effective medicine and is of great significance
Quinoline is a kind of important compound in azacyclo-, is the mother of many natural products and biologically active drug structure
Core, such as quinoline, chloroquinoline, the peaceful alkali A of camel, camptothecine.Wang etc. is in Bioorg Med Chem Lett, and 2011,21:2313
In report from a kind of isolated novel quinoline I of streptomyces sp.Neau50 to A549 tumour cells
IC50 for 29.3ug/mL, be a kind of good tumour lead compound.It is constantly studied by drug scholars, largely
Quinoline derivatives are synthesized, and the bioactivity with official, such as：It is antitumor, antibacterial, anti-malarial, anti-asthma,
Antiplatelet gathers isoreactivity.Therefore, quinoline obtains the concern of more and more researchers.
Invention content
For the problems of the prior art, the present invention provides a kind of quinoline, the quinoline provided have compared with
High medical value, for handling, treating or mitigate metastatic breast cancer and postclimacteric women advanced breast cancer.
For realization more than technical purpose, the technical scheme is that：A kind of quinoline, it is characterised in that：It is described
Quinoline is 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester or its hydrate, prodrug and pharmaceutically acceptable
Salt, structural formula is：It is denoted as compound III.
The preparation method of the quinoline, with 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine) Malaysia
Diethyl phthalate (II) is raw material, adds in catalyst and organic solvent, using one kettle way, the product 6- last of the ten Heavenly stems is prepared through ring-closure reaction
Oxygroup -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester, i.e. compound III, reaction process are as follows：
The catalyst uses organic acid, addition and 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine)
The ratio of diethyl maleate mole is 1-20.
Preferably, the catalyst and 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine) maleic acid diethyl
The ratio of ester mole is 1-3.
Also added with organic solvent during the one pot reaction, the organic solvent using organic carboxyl acid, chloroform,
One kind in dichloromethane or toluene.
The ratio of the mole for adding in volume and raw material of the organic solvent is 800-1200mL/mol, as excellent
Choosing, the ratio of the mole for adding in volume and raw material of organic solvent is 1184-1480mL/mol.
The reaction temperature of the one kettle way is 70-80 DEG C, reaction time 3-8h.
The reaction process is tracked using thin-layer chromatography.
After the one pot reaction, reaction solution is evaporated removal organic solvent, then catalyst neutralisation carries out silica gel
Column chromatography purifies.
The quinoline is in processing, treatment or mitigates metastatic breast cancer and postclimacteric women advanced breast cancer
It is applied in the drug of aspect.
A kind of pharmaceutical composition using compound III and its hydrate as active constituent, and is equipped with prodrug, pharmaceutically may be used
The salt or pharmaceutically acceptable carrier of receiving.
The dosage form of described pharmaceutical composition is using common formulations in the pharmacies such as tablet, capsule, pill.
Pharmaceutically acceptable carrier refers to the carrier of pharmaceutical field routine, refers to one or more inert, non-toxic
Solid or liquid filler material, diluent, auxiliary agent etc., they do not have an effect with reactive compound or patient.
From the above, it can be seen that the present invention has advantages below：
1. quinoline provided by the invention has higher medical value, for handling, treating or mitigate metastatic
Breast cancer and postclimacteric women advanced breast cancer.
2. the present invention using one kettle way as preparation method, not only with good reaction efficiency and reaction stability, and
And side reaction is few, purity is high.
3. the present invention recycles organic solvent by the way of being evaporated, can solve the pollution problem of organic solvent, accord with
Current environmental requirement is closed, while extent of reaction is tracked using thin-layer chromatography, reaction can effectively be controlled to carry out, it is effective to ensure
React high efficiency.
Description of the drawings
Fig. 1 is the hydrogen spectrum nuclear-magnetism figure of 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester III in the embodiment of the present invention 1.
Fig. 2 is the carbon spectrum nuclear-magnetism figure of 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester III in the embodiment of the present invention 1.
Fig. 3 is the DEPT spectrum spectrograms of 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester III in the embodiment of the present invention 1
Specific embodiment
With reference to Fig. 1 and Fig. 2, the specific embodiment that the present invention will be described in detail, but the claim of the present invention is not done
Any restriction.
Embodiment 1
As depicted in figs. 1 and 2, successively by 9.26 grams of 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine) Malaysia
Diethyl phthalate (0.02mol), 30 milliliters of trifluoroacetic acid are added in 100 milliliters of three mouthfuls of reaction bulbs, calorify 75 DEG C of reactions, thin
Layer chromatography tracing detection reacts (solvent：Ethyl acetate：Petroleum ether=1：3), reaction in about 5 hours terminates.Trifluoro is recovered under reduced pressure
Acetic acid adds in 50 milliliters of dichloromethane, and 20% sodium hydrate aqueous solution is added dropwise and is adjusted to neutrality, washes, dry, filtering, and removing is molten
Agent, residue column chromatography purification (eluant ethyl acetate：Petroleum ether=1：6), obtain 5.85 grams of 6- decyloxy -7- ethyoxyls -
Quinoline-3-carboxylic acid ethyl ester, 52-53 DEG C of fusing point, yield 72.9%.
After testing, the hydrogen of 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester manufactured in the present embodiment composes nuclear-magnetism figure such as
Shown in Fig. 1, carbon spectrum nuclear-magnetism figure is as shown in Figure 2, DEPT spectrums are as shown in Figure 3：
1HNMR(δ,ppm,400MHz,CDCl3)：9.207 (s, 1H ,-C=CH-)；8.591 (s, 1H ,-C=CH-)；
7.388 (s, 1H ,-C=CH-)；7.067 (s, 1H ,-C=CH-)；4.440-4.423(q,2H,-CH2-)；4.258-4.209
(q,2H,-CH2-)；4.106-4.075(t,2H,-CH2-)；1.909-1.874(m,2H,-CH2-)；1.543-1.245(m,
20H,-CH2-,-CH3),0.852-0.836(t,3H,CH3)
13CNMR(δ,ppm,100MHz,CDCl3)：165.77；154.05；150.03；147.83；136.25；122.34；
121.29；108.43；106.89；69.10；64.53；61.10；31.87；29.53；29.50；29.34；29.29；28.84；
25.95；22.64；14.42；14.33；14.07.
DEPT135CNMR(δ,ppm,100MHz,CDCl3)：147.8；136.25；108.38；106.85；69.08(D)；
64.53(D)；61.09(D)；31.87(D)；29.53(D)；29.50(D)；29.34(D)；29.29(D)；28.84(D)；25.95
(D)；22.64(D)；14.42；14.33；14.07.
Embodiment 2- embodiments 4
By 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine), (0.02 rubs 9.26 grams of diethyl maleate successively
You), organic carboxyl acid 30mL be added in 100 milliliters of four mouthfuls of reaction bulbs, be stirred to react under certain temperature, thin-layer chromatography tracking
Alkali neutralization, liquid separation is added dropwise to terminating in detection reaction, and solvent, silica gel column chromatography (eluant, eluent is recovered under reduced pressure after dry in washing：Second
Acetoacetic ester:Petroleum ether=1:6) it, weighs, calculates yield, as a result such as table 1.
The product yield of embodiment 2- embodiments 4
| Catalyst | Yield (%) | Reaction temperature | |
| Embodiment 2 | Trifluoro formic acid | 73 | 78 |
| Embodiment 3 | Acetic acid | 20 | 78 |
| Embodiment 4 | Formic acid | 35 | 78 |
Embodiment 5- embodiments 8
By 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine), (0.02 rubs 9.26 grams of diethyl maleate successively
You), the addition of 5 milliliters of trifluoroacetic acid, in four mouthfuls of reaction bulbs of 30 milliliters to 100 milliliters of appropriate solvent, stirred under certain temperature
Reaction, thin-layer chromatography tracing detection are reacted to terminating, and alkali neutralization, liquid separation is added dropwise, and solvent, silicon is recovered under reduced pressure after dry in washing
Plastic column chromatography (eluant, eluent：Ethyl acetate:Petroleum ether=1:6) it, weighs, calculates yield,
The product yield of embodiment 5- embodiments 8
| Organic solvent | Yield (%) | Reaction temperature | |
| Embodiment 5 | Dichloromethane | 58 | 78 |
| Embodiment 6 | Dichloroethanes | 62 | 78 |
| Embodiment 7 | Toluene | 43 | 78 |
| Embodiment 8 | Trifluoroacetic acid | 72 | 78 |
9 anti tumor activity in vitro determination experiment of embodiment：
Experiment is carried out using international mtt assay, and tumor cell in vitro inhibitory activity experiment is carried out to compound III：
First, the breast cancer cell BS524 (T47D) of 2 × 104 exponential phases, 3 multiple holes, cell are inoculated in 96 porocyte plates
After adherent, various concentration sample to be tested is added, 7 drug concentration gradients (unit ug/mL) are set altogether, concentration is respectively：
1.0,5.0,10,20,30,40 and 50 chemical compounds I sample sets；After 72 hours, add in 5mg/mL's in 96 orifice plate corresponding apertures
MTT solution 20uL continue culture 3 hours, discard supernatant in orifice plate, add in the DMSO dissolvings of 100uL, are detected using microplate reader
Light absorption value under 570nm wavelength simultaneously calculates sample to be tested and is to the half-inhibition concentration IC50, IC50 of cell growth
18.05ug/mL.The experimental results showed that compound has breast carcinoma cell strain apparent inhibiting effect, swell to develop new resisting
Tumor medicine provides lead compound, is of great significance.
It is understood that above with respect to the specific descriptions of the present invention, it is merely to illustrate the present invention and is not limited to this
The described technical solution of inventive embodiments.It will be understood by those of ordinary skill in the art that still the present invention can be carried out
Modification or equivalent replacement, to reach identical technique effect；As long as meeting using needs, all protection scope of the present invention it
It is interior.
Claims (10)
1. a kind of quinoline, it is characterised in that：The described quinoline is 6- decyloxy -7- ethoxy yl-quinoline -3- carboxylics
Acetoacetic ester or its hydrate, prodrug and pharmaceutically acceptable salt, structural formula are：
It is denoted as compound III.
2. a kind of quinoline according to claim 1, it is characterised in that：The preparation method of the quinoline,
With 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine) diethyl maleate (II) for raw material, catalyst is added in, is used
Product 6- decyloxies -7- ethyoxyls-quinoline-3-carboxylic acid ethyl ester, i.e. compound III is prepared through ring-closure reaction in one kettle way,
Reaction process is as follows：
3. a kind of quinoline according to claim 2, it is characterised in that：The catalyst uses organic acid, adds
The ratio for entering amount and 2- ((4- decyloxy -3- Ethoxyphenylaminos) methine) diethyl maleate mole is 1-20.
4. a kind of quinoline according to claim 3, it is characterised in that：The catalyst and 2- ((4- decyloxies-
3- Ethoxyphenylaminos) methine) diethyl maleate mole ratio be 1-3.
5. a kind of quinoline according to claim 2, it is characterised in that：The organic solvent using organic carboxyl acid,
One kind in chloroform, dichloromethane or toluene.
6. a kind of quinoline according to claim 5, it is characterised in that：During the one pot reaction also added with
Organic solvent, the ratio of the mole for adding in volume and raw material of the organic solvent is 800-1200mL/mol, as excellent
Choosing, the ratio of the mole for adding in volume and raw material of organic solvent is 1184-1480mL/mol.
7. a kind of quinoline according to claim 5, it is characterised in that：The reaction temperature of the one kettle way is 70-
80 DEG C, reaction time 3-8h.
8. a kind of quinoline according to claim 2, it is characterised in that：The reaction process using thin-layer chromatography with
Track；After the one pot reaction, reaction solution is evaporated removal organic solvent, then catalyst neutralisation carries out silica gel column layer
Analysis purification.
9. a kind of application of quinoline as described in claim 2-8, it is characterised in that：The quinoline is being located
It is applied in drug in terms of reason, treatment or mitigation metastatic breast cancer and postclimacteric women advanced breast cancer.
10. a kind of pharmaceutical composition using compound III and its hydrate as active constituent, and is equipped with prodrug, can pharmaceutically connect
The salt or pharmaceutically acceptable carrier received；The dosage form of described pharmaceutical composition is using normal in the pharmacies such as tablet, capsule, pill
Use dosage form.
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| CN201711316481.7A CN108191756B (en) | 2017-12-12 | 2017-12-12 | Quinoline derivative and preparation method and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003000682A1 (en) * | 2001-06-25 | 2003-01-03 | Merck & Co., Inc. | (pyrimidyl)(phenyl)substituted fused heteroaryl p38 inhibiting and pkg kinase inhibiting compounds |
| CN1169795C (en) * | 1996-10-01 | 2004-10-06 | 协和发酵工业株式会社 | Nitrogenous heterocyclic compounds |
| WO2006117660A2 (en) * | 2005-05-04 | 2006-11-09 | Clio Pharmaceutical Corporation | Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins |
| CN101012195A (en) * | 2007-02-15 | 2007-08-08 | 常熟市欧亚吉生物医药研究所 | Method of preparing 4-hydroxy-6-decyloxy-7-ethoxy-3-quinoline carboxylic acid ethyl ester |
-
2017
- 2017-12-12 CN CN201711316481.7A patent/CN108191756B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1169795C (en) * | 1996-10-01 | 2004-10-06 | 协和发酵工业株式会社 | Nitrogenous heterocyclic compounds |
| WO2003000682A1 (en) * | 2001-06-25 | 2003-01-03 | Merck & Co., Inc. | (pyrimidyl)(phenyl)substituted fused heteroaryl p38 inhibiting and pkg kinase inhibiting compounds |
| WO2006117660A2 (en) * | 2005-05-04 | 2006-11-09 | Clio Pharmaceutical Corporation | Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins |
| CN101012195A (en) * | 2007-02-15 | 2007-08-08 | 常熟市欧亚吉生物医药研究所 | Method of preparing 4-hydroxy-6-decyloxy-7-ethoxy-3-quinoline carboxylic acid ethyl ester |
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