CN103936682A - Aminemethylene-quinoxaline-1,4-dioxide as well as preparation method and application thereof - Google Patents
Aminemethylene-quinoxaline-1,4-dioxide as well as preparation method and application thereof Download PDFInfo
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- CN103936682A CN103936682A CN201410135755.2A CN201410135755A CN103936682A CN 103936682 A CN103936682 A CN 103936682A CN 201410135755 A CN201410135755 A CN 201410135755A CN 103936682 A CN103936682 A CN 103936682A
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- quinoxaline
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- methane
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
- C07D241/52—Oxygen atoms
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Abstract
The invention discloses a method for preparing aminemethylene-quinoxaline-1,4-dioxide. The method comprises the following step of carrying out a Mannich reaction between mequindox and bi-(dimethylamine) methane or bi-(diethylamine) methane or bi-(piperidine) methane to generate aminemethylene-quinoxaline-1,4-dioxide. The synthetic aminemethylene-quinoxaline-1,4-dioxide (a, b, c) is a novel veterinary medicine synthesized on the basis of quinazoline by the applicant, is insoluble in water and can be dissolved in dioxane and dimethyl sulfoxide, and the primary ring of the structure is the same as that of an olaquindox structure (quitazine). The activity experiment proves that the aminemethylene-quinoxaline-1,4-dioxide has high bacteriostatic activity on Escherichia coli C83-1, Pseudomonas aeruginosa C79-6, salmonella 1014 and Klebsiella 219. The prepared piperidinemethylene-quinoxaline-1,4-dioxide (c) is the best, can serve as a novel veterinary medicine and is applied in the aspect of treating bacterial diseases.
Description
Technical field
The present invention relates to a kind of quinoxaline compound and preparation method thereof, and the application in antibacterials.
Background technology
Quinoxaline-Isosorbide-5-Nitrae-dioxy compound derivatives has that toxicity is low, side effect is little, dosage is low, can be applied to the long term in feed, for livestock breeding industry has been brought into play huge effect as antibacterial growth-promoting additive.As carbadox (Carbadox), olaquindox (Olaquindox), methlacetylquinoxalinediode (Maquindox) etc. have better activity to Gram-negative bacteria, positive bacteria, nitrogen is had to delay effect and protein assimilation, to improving feed conversion rate and promoting growth to have unusual effect simultaneously.Therefore, be widely used in various animal-feeds, be mainly used in growth promotion, improve efficiency of feed utilization and prevention cub diarrhoea, improve the surviving rate of cub, fowl, be sometimes also used for the treatment of fowl cholera, white dysentery, the diseases such as grice diarrhoea.Since the Haddadin of nineteen sixty-five Beirut,Lebanon (Beirut) and Issidorides have delivered first piece of article of Beirut reaction, the patent that existing hundreds of application Beirut reacts synthetic is come out and synthetic not next thousand kinds of new nitrogen heterocyclic.But due to potential " three cause " problem, various countries have carried out large quantity research to the safety applications of quinoxaline medicine, in succession formulated strict rules, drug manufacture, using method, usage quantity etc. have been made to strict regulation, and the new special-purpose substitute of livestock and poultry of continuous research and development.In fact in the past in more than 50 year, because animal-feed application quinoxaline has improved production efficiency, reduced livestock product, the cost of meat particularly, has improved the wholesomeness of meat, to the mankind, provides a large amount of cheapnesss and the livestock product of high-quality.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, and a kind of new quinoxaline compound with pharmaceutical use---amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide is provided;
Another object of the present invention is to provide the preparation method of above-claimed cpd;
Another object of the present invention is to provide the application of above-claimed cpd.
Object of the present invention is carried out specific implementation by the following technical programs:
Amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide, its structural formula is as I:
Wherein,
When
time, be compound a, this compound name is called: dimethylamine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide;
When
time, be compound b, this compound name is called: diethylamine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide;
When
time, be compound c, this chemical combination title thing is: piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide.
A kind of amine methylene radical-quinoxaline-1, the preparation method of 4-dioxide is: mequindox and two-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane generation Mannich reaction generation amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide.
Preferably, the medium of described Mannich reaction is acid reaction medium, and pyridine is as reaction solvent.
Preferably, described acidic medium adopts and adds the method for concentrated hydrochloric acid to obtain, wherein, and described mequindox: pyridine: two-(dimethylamine) methane: concentrated hydrochloric acid (W: V: V) be 4.4g:40mL:0.15mL:0.8mL.
Preferably, the temperature of described Mannich reaction is controlled at 55 ℃, and the reaction times is controlled as 2h.
As the preferred version of aforesaid method, concrete operation step is as follows:
Precision takes mequindox 4.4g and is dissolved in 40ml pyridine, and heating for dissolving splashes into two-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane 0.15mL and drips the dense HCl of 0.8mL, stirs; Temperature is controlled at 55 ℃, and the reaction in 2 hours that refluxes finishes, and is spin-dried for solvent, with saturated NaCl, concentrated solution is washed till to separating funnel, ethyl acetate is repeatedly extraction on a small quantity, combining extraction liquid, put into anhydrous Na 2SO4 dry, filter, be spin-dried for, volatilize solvent, obtain crude product, gained crude product is separated with silicagel column, obtains dendroid yellow crystals, is end product.
Further preferred, during heating for dissolving, adopt whiteruss as heating medium.
Described pair-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane are prepared as follows and form:
Under ice-water bath is cooling, add the HCHO of 15ml37% in reaction flask, under stirring, the dimethylamine that contains 0.37mol with dropping funnel dropping or the aqueous solution of diethylamine or piperidines, after dropwising, stirring at room 30min, then adds solid NaOH to form two-phase to solution, separating funnel is divided into two-layer, dry with solid NaOH, place and filter, air distillation, collect the cut of 83 ℃, obtain.
Described mequindox is prepared as follows and forms:
In benzofuraxan, add excessive methyl ethyl diketone 18g, water-bath is warmed to molten, under jolting, adds triethylamine, warm several minutes again, cooling under room temperature, place, crystallization, separates out a large amount of yellow crystals, suction filtration after 10h gradually, collect crystallization, a small amount of water washing, dry, through dehydrated alcohol recrystallization, obtain aureus needle crystal, i.e. mequindox.
Piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (c) is as the application of the veterinary drug for the treatment of bacteriosis.
In order to further illustrate essence of the present invention, applicant has carried out the relevant test of pesticide effectiveness to the dimethylamine preparing (diethylamine, piperidines) methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide.
(1), compound a, b, the extracorporeal bacteria inhibitor test of c
1 materials and methods
1.1 test drug quinoxalines (a, b, c) are provided by Lanzhou Livestock and Animal Drug Inst., Chinese Academy of Agricultural Science with Quinocetone (MBQO), and purity is more than 98%.
1.2 test strain
Intestinal bacteria Escherichia coliC
83-1purchased from China Veterinary Drugs Supervisory Inst., Salmonellas Salmonlla C
79-6purchased from China Veterinary Drugs Supervisory Inst., Pseudomonas aeruginosa Pseudomonas qeruginosa
1014purchased from Beijing biologics, identify institute, klebsiella Klebsialla
219purchased from Beijing biologics, identify institute.
1.3 test method
1.3.1 the comparison of In Vitro Bacteriostasis effect: adopt cylinder plate method, to dissolve nutrient agar and be cooled to 50 ℃, add appropriate test bacterium liquid and nutrient agar to mix, draw 15ml and be placed in plate, after solidifying, Oxford cup is positioned on plate bacterium layer, every glass adds concentration is liquid 0.2ml, then plate is built, in 37 ℃ of constant temperature culture 18-24h, used vernier caliper measurement antibacterial circle diameter.Fungistatic effect judging criterion: D≤8mm is insensitive, and 8mm < D≤13 are low responsive, and 13mm < D≤19 are medium sensitivity, and 19mm < D is extremely sensitive.
The optimum conditions of 1.4 piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (c)
Material ratio mequindox is chosen in this experiment: two-(piperidines) methane (X
1) 1:2-1:5.5, reaction times (X
2) 0.5-3.5h, temperature of reaction (X
3) 0-65 ℃ and catalytic amount (X
4) 8 levels of a 0.5-2.0ml4 factor test, plan U
8* (8
4) table design.
2 results and discussion
The extracorporeal bacteria inhibitor test of 2.13-methyl-2-(amido phenylethylene keto)-quinoxaline-Isosorbide-5-Nitrae-dioxide (a, b, c), Quinocetone the results are shown in Table 1.
The comparison (mm) of the In Vitro Bacteriostasis effect of table 1. target compound
x±s,n=5,p<0.05Vs?control
As can be known from Table 1, Quinocetone and compound a, b, c has enhancing in varying degrees, particularly c obviously to increase colibacillary inhibition zone to testing four kinds of bacteriostasises used.See Fig. 7 and 8.
The physico-chemical property of 2.2 compound c
Piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (c) is new compound, does not also have the report of its physico-chemical property.Herein its solubleness and fusing point are measured.This product is yellow powder, and odorless dissolves in pyridine, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), is slightly soluble in dioxane, acetone, water insoluble, chloroform, benzene.Fusing point 203-205 ℃.
The synthesis condition of 2.3 homogeneous design optimizations " compound c "
According to single factor experiment, material ratio mequindox is chosen in this experiment: two-(two piperidines) methane (X1) 1:2.0-1:5.5 reaction times (X2) 1-4h, 0-65 ℃ of temperature of reaction (X3) and 8 levels of 0.4-1.8ml4 factor of catalytic amount (X4) are tested, intend with U8 * (84) table design, factor and level are in Table 1.
Factor and the level of table 1. compound c chemosynthesis homogeneous design
By table, can see that optimum reaction condition is, mequindox: pyridine: two-(piperidines) methane: concentrated hydrochloric acid (W: V: V) be 4.4g:40mL:0.15mL:0.8mL.At 55 ℃, stir 2h.
Beneficial effect of the present invention:
Amine methylene radical-quinoxaline-1 that the present invention is synthetic, 4-dioxide (a, b, c) is a kind of novel veterinary drug being synthesized on the basis of quinoline by the applicant, water insoluble, dissolve in dioxane and methyl-sulphoxide, its structure female ring is identical with olaquindox structure female ring (quinoline is favored with piperazine).Its activity experiment shows, to intestinal bacteria C
83-1, Pseudomonas aeruginosa C
79-6, Salmonellas
1014, klebsiella
219deng thering is good bacteriostatic activity.Wherein, piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (c) prepared by the present invention is best, can be used as a kind of novel veterinary drug, aspect treatment bacteriosis, is being applied.Synthetic method of the present invention is simple, and by product is few, and productive rate is high, and mild condition is applicable to large-scale industrial production.
Accompanying drawing explanation
Accompanying drawing is used to provide a further understanding of the present invention, and forms a part for specification sheets, for explaining the present invention, is not construed as limiting the invention together with embodiments of the present invention.In the accompanying drawings:
Fig. 1 is cylinder plate method bacteriostatic experiment plate photo;
Fig. 2 is the photo of vernier caliper measurement antibacterial circle diameter in cylinder plate method bacteriostatic experiment;
Fig. 3 is compound a hydrogen nuclear magnetic resonance spectrogram;
Fig. 4 is compound a carbon-13 nmr spectra figure;
Fig. 5 is compound b hydrogen nuclear magnetic resonance spectrogram;
Fig. 6 is compound b carbon-13 nmr spectra figure;
Fig. 7 is compound c hydrogen nuclear magnetic resonance spectrogram;
Fig. 8 is compound c carbon-13 nmr spectra figure.
Embodiment
Below in conjunction with accompanying drawing, the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
Embodiment 1: dimethylamine (diethylamine, piperidines) methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide
The preparation of dimethylamine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (a)
1) two-(dimethylamine) methane is synthetic
Under ice-water bath is cooling, add the HCHO of 15ml37% in reaction flask, under stirring, with dropping funnel, drip 0.37molNH (CH
3)
2the aqueous solution (50ml, 33wt%), after dropwising, stirring at room 30min, then adds solid NaOH to form two-phase to solution, and separating funnel is divided into two-layer, dry with solid NaOH, places and filters, and air distillation, collects 83 ℃ of cuts.
2) mequindox is synthetic
Benzofuraxan (10g, 73.5mmol), adds excessive methyl ethyl diketone 18g, and water-bath is warmed to molten, adds triethylamine 40ml under jolting, more warm several minutes, cooling under room temperature, place, crystallization, separates out a large amount of yellow crystals after 10 hours gradually.Suction filtration, collects crystallization, and a small amount of water washing is dry, output 11g, and dehydrated alcohol recrystallization, obtains aureus needle crystal, productive rate 68%.
3) end product is synthetic
Precision takes mequindox 4.4g and is dissolved in 40ml pyridine, whiteruss heating for dissolving, splash into two-two and 10 dense HCl of (dimethylamine) methane, stir, reflux, TLC tracks to reaction to be finished, be spin-dried for solvent, with saturated NaCl, concentrated solution be washed till to separating funnel, ethyl acetate is repeatedly extraction on a small quantity, combining extraction liquid, puts into anhydrous Na
2sO
4dry, filter, be spin-dried for, volatilize solvent, obtain crude product, gained crude product is separated with silicagel column, obtains dendroid yellow crystals, i.e. compound a.Its nuclear magnetic spectrogram is referring to Fig. 3,4.
Embodiment 2:
The preparation of diethylamine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (b)
Its preparation method and embodiment 1 are with reference to embodiment 1, and difference part is: in step 1, adopt diethylamine to replace dimethylamine, the final compound b that obtains.Its nuclear magnetic spectrogram is referring to Fig. 5,6.
Embodiment 3:
The preparation of piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide (c)
Its preparation method is substantially the same manner as Example 1, and difference part is: in step 1, adopt piperidines to replace dimethylamine, the final compound c that obtains.Its nuclear magnetic spectrogram is referring to Fig. 7,8.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, its technical scheme that still can record aforementioned each embodiment is modified, or part technical characterictic is wherein equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide, its structural formula is as I:
（Ⅰ）
Wherein,
。
2. amine methylene radical-quinoxaline-1, the preparation method of 4-dioxide, it is characterized in that: mequindox and two-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane generation Mannich reaction generation amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide.
3. the preparation method of amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide according to claim 2, is characterized in that: the medium of described Mannich reaction is acid reaction medium, and pyridine is as reaction solvent.
4. amine according to claim 3 methylene radical-quinoxaline-1, the preparation method of 4-dioxide, it is characterized in that: described acidic medium adopts and adds the method for concentrated hydrochloric acid to obtain, wherein, described mequindox: pyridine: two-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane: concentrated hydrochloric acid is 4.4g:40mL:0.15mL:0.8mL.
5. according to the preparation method of the amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide described in claim 2-4 any one, it is characterized in that: the temperature of described Mannich reaction is controlled at 55 ℃, the reaction times is controlled as 2h.
6. amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide preparation method according to claim 5, is characterized in that: concrete operation step is as follows:
Precision takes mequindox 4.4g and is dissolved in 40ml pyridine, and heating for dissolving splashes into two-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane 0.15mL and drips the dense HCl of 0.8mL, stirs; Temperature is controlled at 55 ℃, and the reaction in 2 hours that refluxes finishes, and is spin-dried for solvent, with saturated NaCl, concentrated solution is washed till to separating funnel, and ethyl acetate is repeatedly extraction on a small quantity, and combining extraction liquid, puts into anhydrous Na
2sO
4dry, filter, be spin-dried for, volatilize solvent, obtain crude product, gained crude product is separated with silicagel column, obtains dendroid yellow crystals, is end product.
7. amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide preparation method according to claim 6, is characterized in that: during heating for dissolving, adopt whiteruss as heating medium.
8. according to the amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide preparation method described in claim 6 or 7, it is characterized in that: described pair-(dimethylamine) methane or two-(diethylamine) methane or two-(piperidines) methane are prepared as follows and form:
Under ice-water bath is cooling, add the HCHO of 15ml37% in reaction flask, under stirring, the dimethylamine that contains 0.37mol with dropping funnel dropping or the aqueous solution of diethylamine or piperidines, after dropwising, stirring at room 30min, then adds solid NaOH to form two-phase to solution, separating funnel is divided into two-layer, dry with solid NaOH, place and filter, air distillation, collect the cut of 83 ℃, obtain.
9. according to the amine methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide preparation method described in claim 6 or 7, it is characterized in that: described mequindox is prepared as follows and forms:
In benzofuraxan, add excessive methyl ethyl diketone 18g, water-bath is warmed to molten, under jolting, adds triethylamine, warm several minutes again, cooling under room temperature, place, crystallization, separates out a large amount of yellow crystals, suction filtration after 10h gradually, collect crystallization, a small amount of water washing, dry, through dehydrated alcohol recrystallization, obtain aureus needle crystal, i.e. mequindox.
10. piperidines methylene radical-quinoxaline-Isosorbide-5-Nitrae-dioxide is as the application of the veterinary drug for the treatment of bacteriosis.
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2014
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Application publication date: 20140723 |