CN102898369A - 3-amino-7-bromoquinoline-2-ethyl formate and preparation method thereof - Google Patents
3-amino-7-bromoquinoline-2-ethyl formate and preparation method thereof Download PDFInfo
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- CN102898369A CN102898369A CN2012104339256A CN201210433925A CN102898369A CN 102898369 A CN102898369 A CN 102898369A CN 2012104339256 A CN2012104339256 A CN 2012104339256A CN 201210433925 A CN201210433925 A CN 201210433925A CN 102898369 A CN102898369 A CN 102898369A
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Abstract
The invention provides a new aminoquinoline compound and a preparation method thereof, and in particular relates to 3-amino-7-bromoquinoline-2-ethyl formate and a preparation method thereof and application of the compound in the field of medicinal chemistry. The 3-amino-7-bromoquinoline-2-ethyl formate has good coordination property and relatively high selectivity on metal ions, has pharmacological activity, can be widely applied to synthesis of anti-cancer, anti-virus and anti-fungal medicaments, and particularly can be applied to new medicaments of medicament-resistant plasmodium falciparum strains.
Description
Technical field
The present invention relates to a kind of new aminoquinoline compounds and preparation method thereof, more specifically, the present invention relates to 3-amino-7-bromoquinoline-2-ethyl formate and preparation method thereof.
Background technology
Heterogeneous ring compound has certain biological activity mostly, and quinolines is the heterocycle compound that has biological activity and pharmacologically active concurrently, and wherein, quinolylamine is the important quinoline that has than high biological activity.Studies show that the many medicines with quinolylamine ring are having higher using value aspect treatment abalienation, anti-inflammatory, antibiotic, hypertension, the anti-malarial.In view of its critical role in the pharmaceutical chemistry field, aminoquinolines just more and more receives publicity, and is able to widespread use, and people have carried out a large amount of modification research and applied research take it as the basis.
For example: publication number is to mention among the CN102530216A using aminoquinoline compounds to have antibiotic, antimycotic, antitumor, antiviral, xitix isoreactivity, wherein aminoquinoline compounds be usually used in antitumor, antiviral, the aspects such as chitinase inhibitors.And be to have mentioned quinolylamine among the CN101346381A to have to antimalarial effect at publication number.Publication number is that the Chinese invention patent application of CN101346381A has just disclosed the application of a kind of 4-aminoquinoline derivatives in anti-malaria medicaments, publication number is that the Chinese invention patent application of CN101239945A has disclosed the purposes of amino quinoline derivatives as the antagonist of Adenosine Receptors A3 blood subgroup, publication number is that the Chinese invention patent application of CN101686973A has disclosed the application of 4-quinolylamine-3-nitrile in the leukemia for the treatment of imatinib resistant, and publication number is that the Chinese invention patent application of CN102249997A has disclosed 4-substituted benzene aminoquinoline compounds and suppressing the application in the tumour of EGF-R ELISA (EGFR) high expression level.These patents are as background technology document of the present invention, are introduced into and as a reference at this.
Because the derivative anti-malarial of quinolylamine is effective, and for the plasmodium falciparum strain of anti-chloroquine activity is arranged also, so can be applied to resist in the new drug of drug resistant falciparum malaria protozoon strain, in anti-malarial, hypertension and antibiotic medicine, occupy at present very important status.In addition, quinolylamine has good coordination and relatively high selectivity to metal ion, can be used as the embedded body, fluorescent probe of biomacromolecule etc., has in molecular biology widely and uses.The aminoquinolines with pharmacologically active that the positive active development of people is new, and the synthetic method of this class aminoquinoline compounds sought to update, for human health is made larger contribution.
Summary of the invention
The object of the invention is to design a kind of new amino quinoline derivatives with pharmacologically active, and the preparation method who is easy to realize is provided.The contriver is by constantly test discovery, 3-amino-7-bromoquinoline-2-ethyl formate (C
12H
11BrN
2O
2) pharmacological activity with desirable, this is never by correlation technique bibliographical information mistake.The chemical structural formula of 3-amino-7-bromoquinoline-2-ethyl formate is as follows:
3-amino-7-bromoquinoline-2-ethyl formate molecular weight 295.Through identifying that its proton nmr spectra is (400MHz, CDCl
3): δ 1.50-1.53 (t, 3H), 4.53-4.59 (q, 2H), 7.35 (s, H), 7.44-7.46 (d, 1H), 7.52-7.54 (dd, 1H), 8.29-8.30 (m, 1H), mass spectrum are (MS) M+2297.
By biological experiment checking, coordination and relatively high selectivity that 3-amino-7-bromoquinoline-2-ethyl formate is good to metal ion have pharmacologically active, can be widely used in during anticancer, antiviral, antimycotic medicine synthesizes.Because the derivative anti-malarial of quinolylamine is effectively, and also has activity for the plasmodium falciparum strain of anti-chloroquine, so can be applied to resist in the new drug of drug resistant falciparum malaria protozoon strain.
Therefore, the pharmacy acceptable salt of 3-amino-7-bromoquinoline-2-ethyl formate, for example inorganic acid salt and organic acid salt, amino acid whose salt also consist of a part of the present invention.Better salt is hydrochloride, phosphoric acid salt, vitriol, Citrate trianion and fumarate.
Compound of the present invention can use with the form of capacity formulation, and the character of use depends on selected medication.Particular case or the state of the disease for the treatment of as required, the amount that patient accepts compound of the present invention is the effectively upper and well-tolerated for the treatment of, this can be determined by those skilled in the art.For example, per daily dose is approximately 1 to 60mg/kg, is preferably 3 to 30mg/kg.
According to conventional methods, adopt compatible pharmaceutically acceptable vehicle or carrier compound of the present invention can be made pharmaceutical compositions.For example, pharmaceutical compositions comprises capsule, tablet, syrup, pulvis and granula, make instant solution, injectable, rectum gives and nose in the preparation that gives.Preferred medication is oral.
Vitro test the effect of compound of the present invention for and anti-chlorine caye pernicious scar protozoon strain responsive to chlorine, their half inhibiting rate IC
50Value is between 10 to 200ng/ml, and the vitro test result has shown validity equally.In addition, the toxicity of these compounds in mammalian cell (WEHI clones 13 mouse cells) is very low, its half inhibiting rate IC
50＞10000nM.
Another object of the present invention is to, the preparation method of 3-amino-7-bromoquinoline-2-ethyl formate is provided, compare with existing method of producing amino quinoline derivatives, the method operational path is advanced, simple to operate, reaction conditions is gentle, comprehensive yield is very desirable, environmental friendliness, production cost are low, applicable to testing laboratory's preparation and industrial-scale production.
Concrete, preparation 3-amino-7-bromoquinoline-2-ethyl formate adopts following operational path: raw material 2-amino-4-bromo-benzoic acid is reduced into alcohol, then alcohol is oxidized to aldehyde, close ring with ethyl bromide acetone at last and obtain final product.Described operational path can be expressed as following steps:
A. do raw material with 2-amino-4-bromo-benzoic acid, reduction obtains 2-amino-4-bromobenzene methyl alcohol;
B. the product oxidation that steps A is obtained obtains 2-amino-4-bromobenzaldehyde;
C. with resulting product and ethyl bromide acetone reaction, close ring and obtain 3-amino-7-bromoquinoline-2-ethyl formate.
The employed reductive agent of steps A can be selected from iron powder, zinc powder, Lithium Aluminium Hydride, sodium borohydride etc., is preferably the combination of 1: 1 sodium borohydride of mol ratio and boron trifluoride diethyl etherate.
The employed oxygenant of step B can be selected from FeCL
3, KMnO
4Or MnO
2, being preferably activated manganese dioxide, oxygenant uses as slightly excessive.
Among the step C, preferably use pyridine to accelerate ring closure reaction, and add ethyl esterification generation ethyl ester, adding tetramethyleneimine provides the required carbochain of pass ring and the amino of product.
Be understood that, what more than provide is preferred reaction conditions and the reaction scheme that realizes 3-amino-7-bromoquinoline-2-ethyl formate preparation method, those skilled in the art are according to the description of specification sheets, can understand reaction scheme of the present invention and principle, thereby in the situation of not paying creative work, can select scheme similar or that be equal to, and can regulate reaction conditions (such as temperature, time, strength of solution etc.) according to the art technology knowledge of grasping and practical experience, obtain substantially the same result.In addition, the bound of the scope that more than provides should not be considered as absolute threshold, and in other words, reaction might also can be carried out under the condition outside the preferable range, but effect does not reach best.Therefore, it is limiting the scope of the invention that top generality explanation and following preferred implementation should not be considered as, but in order to provide the present invention is understood better, and protection scope of the present invention should be as the criterion with the content that claim limits.
Description of drawings
Included accompanying drawing be the invention provides further understanding in order to give, and is included in the specification sheets and forms a specification sheets part, illustrates embodiments of the present invention and be used from specification sheets one to explain principle of the present invention.
In the accompanying drawings:
Fig. 1 is the synthetic route synoptic diagram of the preferred embodiment for the present invention of embodiment 1-3.
Embodiment
Adopting following embodiment is for preferred version of the present invention is described, the technology of operational excellence in the present invention's practice that those skilled in the art are to be understood that disclosed technology in the following embodiment represents that inventors of the present invention find, these technology can artificially consist of the preference pattern of the present invention's practice.Yet, according to content disclosed by the invention, those skilled in the art it should also be understood that: in the situation that does not depart from aim of the present invention, principle and essence, can carry out many changes and these to disclosed particular and change and still can obtain identical or similar result.
Synthesizing of embodiment 1:2-amino-4-bromobenzene methyl alcohol
With 60g NaBH
4Add in the 300mL tetrahydrofuran (THF) (THF) mechanical stirring.Under ice-water bath, in solution, add 100g2-amino-4-bromo-benzoic acid, then drip the 27mL boron trifluoride ether solution, and the control temperature is below 20 degree.After dropwising reaction solution is risen to room temperature, and reaction is spent the night until raw material reaction is complete.
In reaction solution, drip 300ml MeOH, add again 5N NaOH (200ml) after dropwising, stir about half an hour.With the organic solvent Rotary drying in the reaction solution and be cooled to room temperature, separate out solid, filter, obtain the 2-amino-about 60g[mass spectrum of 4-bromobenzene methyl alcohol crude product (MS) M+1203].Yield 98.7%.
Synthesizing of embodiment 2:2-amino-4-bromobenzaldehyde
Product 60g and 300g Manganse Dioxide that embodiment 1 is obtained add in the 1L dichloromethane solvent, mechanical stirring, and reaction is spent the night.Reaction solution is passed through diatomite, and cross post (sherwood oil: ethyl acetate=5: 1) obtain 2-amino-4-bromobenzaldehyde about 40g[proton nmr spectra (400MHz, CDCl
3): δ 6.72-6.75 (d, 1H), 7.23 (bs, 2H), 7.38-7.42 (dd, H), 7.72-7.73 (d, 1H), 9.77 (s, 1H)].Yield 85.2%.
Synthesizing of embodiment 3:3-amino-7-bromoquinoline-2-ethyl formate
At normal temperatures, 40.8 gram ethyl bromide acetones are dissolved in 192 milliliters of ethanol, slowly splash in the mixed solution of 16 gram pyridines and 200 milliliters of ethanol again, the time reacted completely guaranteeing greater than 30 minutes.Be warmed up to 60 degree reactions after 1 hour, be cooled to normal temperature.
The product 2-amino that adding 40 gram embodiment 2 obtain-4-bromobenzaldehyde adds 32 milliliters of pyridines again, refluxes after 4.5 hours, adds 34.1 gram tetramethyleneimine again, and the 3 hours passes of refluxing are encircled upper amino.The TLC detection reaction (sherwood oil: ethyl acetate=5: 1) finish after, spin off most of ethanol, add water and ethyl acetate extraction.Cross post (sherwood oil: ethyl acetate=5: 1).Be spin-dried for, obtain 19 gram 3-amino-7-bromoquinoline-2-ethyl formates.[proton nmr spectra 400MHz, CDCl
3): δ 1.50-1.53 (t, 3H), 4.53-4.59 (q, 2H), 7.35 (s, H), 7.44-7.46 (d, 1H), 7.52-7.54 (dd, 1H), 8.29-8.30 (m, 1H)].Yield 72.3%.
The pharmacologically active of embodiment 4:3-amino-7-bromoquinoline-2-ethyl formate detects
Vitro test the effect of compound of the present invention for and/or anti-chlorine caye pernicious scar protozoon strain pernicious overgrown with weeds protozoon strain (CQ-S) DI0 and anti-chlorine caye pernicious scar protozoon strain (CQ-R) W2 responsive to chlorine, mainly choose 3-amino-7-bromoquinoline-2-ethyl formate (No.1), 3-amino-7-bromoquinoline-2-ethyl formate hydrochloride (No.2), 3-amino-7-bromoquinoline-2-ethyl formate Citrate trianion (No.3) and 3-amino-7-bromoquinoline-2-ethyl formate fumarate (No.4) as test compound.
Concrete grammar: the bacterial strain D10 of chloroquine sensitivity and the bacterial strain W2 of anti-chloroquine are remained on RPMI1640 (EuroClone, Celbio) and the NaHCO that contains 5% hematocrit (A group positive human red blood cell)
3Among the 24mM, add 10% heat inactivation human plasma A group, 20mM Hepes, 2Mm glutamine.Culture remains on and contains 1%O
2, 5%CO
2, 94%N
237 ℃ of atmosphere in.Product is dissolved among water (chloroquine) or the DMSO, is diluted to substratum subsequently and obtains needed concentration (final concentration of DMSO＜1%, nontoxic to parasite).Compound is distributed on 96 orifice plates (COSTAR) of flat bottom aperture.The asynchronous distribution of culture medium that contains 1-1.5% parasitemia and 1% final concentration hematocrit is configured on the aperture, cultivates 72 hours for 37 ℃.By spectrophotometry (OD
650) activity of measuring lactate dehydrogenase of parasites (pIDH) determines parasitic growing state.Anti-scar disease activity is to suppress half inhibiting rate (IC of half substratum
50) represent
Test result is listed in the table below.
From above result as seen, test compound all has obvious restraining effect to pernicious overgrown with weeds protozoon strain (CQ-S) D10 and anti-chlorine caye pernicious scar protozoon strain (CQ-R) W2, effect even better than traditional therapeutical agent chloroquine.
In addition, the effect of above-claimed cpd of having gone back the body build-in test, the abdominal cavity give with oral compound of the present invention after (per daily dose 3mg/kg), obtained same conclusion, prove they effect and chloroquine quite or better.
Can preparing and carry out here according to content disclosed by the invention, all compositions and/or method open and that require need not to adopt unnecessary experiment.Although described the compositions and methods of the invention with regard to preferred embodiment, but it will be apparent to one skilled in the art that and to make change to each step of method of the present invention or the order between step in the situation that does not depart from concept of the present invention, aim and scope.Some reagent of more specifically, being correlated with on chemistry and the structure can replace reagent described herein to obtain similar result.All these are apparent for a person skilled in the art to substitute and revises within the scope that all is included in the claim definition.
Claims (4)
- Compound with following structural formula with and pharmacy acceptable salt:
- 2. method for preparing the described compound of claim 1, described method adopts following operational path:Steps A. do raw material with 2-amino-4-bromo-benzoic acid, reduction obtains 2-amino-4-bromobenzene methyl alcohol;Step B. obtains 2-amino-4-bromobenzaldehyde with the product oxidation that steps A obtains;Step C. closes resulting product and ethyl bromide acetone reaction ring and obtains 3-amino-7-bromoquinoline-2-ethyl formate.
- 3. method according to claim 2, the employed reductive agent of wherein said steps A is the combination of sodium borohydride and boron trifluoride diethyl etherate.
- 4. method according to claim 2, the employed oxygenant of wherein said step B is activated manganese dioxide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239945A (en) * | 2003-07-31 | 2008-08-13 | 塞诺菲-安万特股份有限公司 | Aminoquinoline derivatives and their use as adenosine a3 ligands |
| CN101346381A (en) * | 2005-10-21 | 2009-01-14 | 尼德医药有限公司 | New anti-malaria derivatives of 4-aminoquinoline |
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- 2012-11-05 CN CN2012104339256A patent/CN102898369A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239945A (en) * | 2003-07-31 | 2008-08-13 | 塞诺菲-安万特股份有限公司 | Aminoquinoline derivatives and their use as adenosine a3 ligands |
| CN101346381A (en) * | 2005-10-21 | 2009-01-14 | 尼德医药有限公司 | New anti-malaria derivatives of 4-aminoquinoline |
Non-Patent Citations (1)
| Title |
|---|
| TAE-GYU NAM ET AL.: "A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor", 《ACS CHEMICAL BIOLOGY》, vol. 6, no. 11, 25 August 2011 (2011-08-25), pages 1214 - 1222 * |
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Application publication date: 20130130 |