CN102558076B - 1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline, as well as preparation method and application of 1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline - Google Patents
1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline, as well as preparation method and application of 1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline Download PDFInfo
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Abstract
The invention discloses 1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline as well as a preparation method and application of the 1-oxygen-2-hydroxylmethyl-3-(1-ethoxyl)-quinoxaline with the formula (I) structure. The product (I) is prepared by the following steps: 1, 4-dioxy-3-methyl-2-(1-ethoxyl) quinoxaline is obtained by reduction of raw material mequindox; mixing the product with acetic anhydride and pyridine to obtain 1,4-dioxy-2-(1-ethoxycarbonyloxyethyl)-3-methyl-quinoxaline; then under the effect of the acetic anhydride,1-oxygen-2-(1-ethoxycarbonyloxyethyl)-3-(1-ethoxycarbonyloxymethyl)-quinoxaline is obtained; 1,4-dioxy-2-(1-hydroxyethyl)-3-hydroxylmethyl -quinoxaline is obtained after oxidation by oxidant and hydrolysis by alkali liquor; and under the reduction by a reductant, the product (I) is obtained through reduction of a reductant, wherein the product (I) can be used as a residual marker for mequindox metabolized in a targeting animal body or used as a standard or a reference sample to determine mequindox residual in animal derived food.
Description
technical field
The invention belongs to animal doctor's pharmacological toxicology and chemosynthesis technical field, be specifically related to a kind of 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxaline and preparation method and application.
Background technology
Mequindox is commonly called as " methlacetylquinoxalinediode "; chemistry by name 1; 4-dioxy-3-methyl-2-ethanoyl-quinoxalines; for carbadox analogue; be the treatment antimicrobial drug first going on the market in China, various bacteria is had to stronger restraining effect, especially to Gram-negative bacteria; as stronger in the restraining effect of pasteurellosis bacillus, intestinal bacteria, Salmonellas, Listeria monocytogenes, be drug of first choice and the specifics of the pig treponema dysentery (pig bloody flux) for the treatment of serious harm pig industry.By large scale application and clinical observation, the feature such as prove that this medicine treatment pig treponema dysentery has that consumption is little, instant effect, curative effect are high, safe and reliable, with low cost, easy to use.Result for the treatment of is better than other treatment medicine.This medicine is for oral administration easily to be absorbed, widely distributed, eliminates rapidly.Be mainly used in intestinal tract infections.Cure mainly the diseases such as enteritis, diarrhoea, fowl cholera, the white scour of chicken, typhoid fever, colibacillosis and rabbit bacterial enteritis of pig treponema dysentery, baby pig pujos blancos, calf paratyphoid, all kinds of domestic animals.Its antifungal mechanism is the synthetic of anti-bacteria thymus nucleic acid (DNA).Because of this medicine determined curative effect and the veterinary clinic widespread use of cheap ，Yi China.Large scale application since nineteen eighty-two.Owing to having reduced, the pig causing because of this disease is dead, weightening finish reduces, feed wastage rate increase the loss causing, and within 1981 to 1986, economic benefit adds up to 6.4 hundred million yuan.But less for the aspect research such as residual in this medicine toxicity, food animal body.Metabolism situation in animal body rarely has report, very few to a lot of situation awareness of this medicine.
Animal derived food veterinary drug residue can cause allergic reaction, bacterial drug resistance, chronic toxic effect etc.Since the-quinoxaline medicine developments of Isosorbide-5-Nitrae-dioxy and promoting, its toxic side effect also receives much concern.Due to the specific toxicity of this class medicine, its use is forbidden or strictly restriction.As carbadox is strong mutagenic compound in microorganism and Mammals test macro, pernicious and innocent tumour incidence significantly increases; Olaquindox also has mutagenicity, and innocent tumour incidence also significantly increases etc.In view of carbadox and olaquindox not good enough in the security of aquaculture, there is potential potential safety hazard.
Pharmacokinetics and the residual research of most of quinoxaline medicine have obtained carrying out, the correlative study that has had many research reports ，Dan Dui China to have the veterinary drug mequindox of independent intellectual property right as quinoxaline medicines such as domestic and international, Quinocetones many to olaquindox, carbadox, quinoline match still belongs to blank.The pharmacokinetics of mequindox and metabolism are residual not yet to be furtherd investigate, also not relevant for the report of the residual marker of mequindox and maximum residue limit(MRL).
Patent CN101648917A(February 17 2010 publication date) a kind of preparation method of primary metabolite of mequindox is disclosed, this product can, for the preparation of the standard substance that detect mequindox metabolism, can be used as and detect mequindox residual marker in animal body.But mequindox major metabolite in pig, chicken body has respectively 8 kinds and 12 kinds.Meanwhile, because mequindox metabolisable form in animal body exists multiple possibility, as one-level metabolism, the multiple metabolisable form such as secondary metabolism.Therefore rely on merely a kind of detected result of primary metabolite, the residual content that can not accurately reflect mequindox, therefore, prior art can only detect metabolism in animal body of mequindox and residual cursorily, can not accurately reflect mequindox metabolism situation in animal body, be unfavorable for that people are to correlative studys such as pharmacokinetics in animal body of mequindox and elimination regularities thereof.
Summary of the invention
The object of the invention is to overcome the deficiency in prior art, mequindox being existed in the metabolism of target animals and the residual toxicologic study of metabolite, a kind of 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines are provided, thereby be that people are to the pharmacology of mequindox, toxicity, and the research such as residual provides standard substance or reference substance in food animal body, facilitate the correlative studys such as pharmacokinetics in animal body of mequindox and elimination regularity thereof, can illustrate mequindox pharmacokinetics, metabolism and elimination regularity in animal body.
Another object of the present invention is to provide described 1-oxygen-2-methylol-3-(1-hydroxyethyl) preparation method of-quinoxalines.
Another object of the present invention is to provide the application in target animals internal metabolism residue detection at mequindox of described quinoxaline compound.
Another object of the present invention is the application of described quinoxaline compound mequindox residue detection in animal derived food.
Above-mentioned purpose of the present invention is achieved by following technical solution:
A compound, chemical name is 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxaline, has structure as shown in formula I:
（Ⅰ）。
A preparation method for described quinoxaline compound, comprises the steps:
(1) in reactor, add respectively mequindox, solvent, at 0 ~ 10 ℃, add reductive agent to mix, stirring reaction at 20 ~ 30 ℃, filters, and obtains product Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl) quinoxaline;
(2) step (1) products therefrom, diacetyl oxide, pyridine are mixed at 0 ~ 10 ℃ to stirring reaction at 10 ~ 100 ℃; After having reacted, except desolventizing, washing, extracts to obtain product Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxaline;
(3) step (2) products therefrom is reacted in diacetyl oxide at 100 ~ 150 ℃, obtain product 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxalines;
(4) product of step (3) gained is mixed at 0 ~ 10 ℃ to stirring reaction at 10 ~ 100 ℃ with solvent and oxygenant; Reacted rear extraction, dry, except desolventizing, after column chromatography, obtain product Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxaline;
(5) product of step (4) gained is mixed at 0 ~ 10 ℃ to stirring reaction at 20 ~ 30 ℃ with alkali, solvent; After having reacted, except desolventizing, filter, washing, dry air, obtains product Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline;
(6) product of step (5) gained and solvent, reductive agent hybrid reaction at 0 ~ 110 ℃ are obtained to product 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines;
Described in step (1), reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
Reductive agent described in step (6) is a kind of in V-Brite B, iron powder and hydrochloric acid, zinc powder and hydrochloric acid, hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride.
As a kind of preferred version, described in step (1), solvent is the mixture of alcohol or alcohol and water, and the reaction times is preferably 0.5 ~ 10 hour; The ratio of described mequindox, reductive agent, solvent is preferably 25g:3 ~ 6g:50 ~ 200mL.
As a kind of most preferably scheme, reaction solvent described in step (1) most preferably is 95 volume % aqueous ethanolic solutions; Reaction times most preferably is 1 hour; The ratio of described mequindox, sodium borohydride, 95 volume % aqueous ethanolic solutions most preferably is 25g:5g:100mL.
As a kind of preferred version, described in step (2), stirring reaction temperature is preferably 20 ~ 30 ℃; Reaction times is preferably 0.5 ~ 10 hour; Described Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, diacetyl oxide, pyridine ratio are preferably 3g:1.5 ~ 5g:10 ~ 100mL.
As a kind of most preferably scheme, in step (2), the reaction times most preferably is 5 hours; Described Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, diacetyl oxide, pyridine ratio most preferably are 3g:1.5g:50mL.
As a kind of preferred version, in step (3), the reaction times is preferably 1 ~ 10 hour; The ratio of described Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines, diacetyl oxide is preferably 10g:5 ~ 50mL.
As a kind of most preferably scheme, in step (3), temperature of reaction most preferably is 145 ℃; Reaction times most preferably is 4 hours; The ratio of Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines, diacetyl oxide most preferably is 10g:10mL.
As a kind of preferred version, described in step (4), stirring reaction temperature is preferably 20 ~ 30 ℃; Reaction oxygenant is preferably oxygen, air, ozone, hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide, metachloroperbenzoic acid, potassium hydrogen persulfate, potassium permanganate; Reaction times is preferably 0.5 ~ 24 hour; The mol ratio of described 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxalines and oxygenant is preferably 1:1 ~ 10.
As a kind of more preferably scheme, described in step (4), react oxygenant and be preferably hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide, metachloroperbenzoic acid.
As a kind of most preferably scheme, described in step (4), react oxygenant and most preferably be metachloroperbenzoic acid; Reaction times most preferably is 8 hours; The mol ratio of 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxalines and oxygenant most preferably is 1:1.2.
As a kind of preferred version, the ratio of Isosorbide-5-Nitrae-dioxy-2-described in step (5) (1-ethoxycarbonyl-oxygen ethyl)-3-ethoxycarbonyl-oxygen methyl-quinoxalines and alkali, solvent is preferably 0.01mol:0.0005 ~ 0.005mol:50 ~ 200mL; Described alkali is preferably salt of wormwood, sodium carbonate, and solvent is preferably the mixed solvent of methyl alcohol, ethanol, methyl alcohol and water or ethanol and water.
As a kind of most preferably scheme, the ratio of Isosorbide-5-Nitrae-dioxy-2-described in step (5) (1-ethoxycarbonyl-oxygen ethyl)-3-ethoxycarbonyl-oxygen methyl-quinoxalines and alkali, solvent most preferably is 0.01mol:0.004mol:50mL; Reaction times most preferably is 3 hours; Described alkali most preferably is salt of wormwood, and solvent most preferably is methyl alcohol and water mixed solvent, and wherein the volume ratio of methyl alcohol and water most preferably is 4:1.
As a kind of preferred version, described in step (6), temperature of reaction is preferably 0 ~ 80 ℃; Reaction times is preferably 0.5 ~ 10 hour; Solvent is preferably one or more the mixture in water, methyl alcohol, ethanol, and the ratio of described Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxalines, reductive agent is preferably 10g:10 ~ 100g.
As a kind of most preferably scheme, described in step (6), temperature of reaction most preferably is 80 ℃; Reaction times most preferably is 1.5 hours; Reductive agent most preferably is V-Brite B, and solvent most preferably is 60 volume % aqueous ethanolic solutions, and the ratio of described Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxalines, V-Brite B most preferably is 1g:10g.
As a kind of preferred version, the preparation method of described quinoxaline compound, comprises the steps:
(1) in reactor, add respectively 25 grams of mequindoxes, 100 milliliter of 95 volume % aqueous ethanolic solution, at 0 ~ 10 ℃, add 5 grams of sodium borohydrides, at 20 ~ 30 ℃, stirring reaction is 1 hour, has reacted rear filtration, obtain Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl) quinoxaline;
(2) 50 milliliters of 3.1 grams of step (1) products therefroms, 1.6 grams of diacetyl oxides, pyridine are mixed at 0 ℃, then at 25 ℃, react 5 hours; After having reacted, remove pyridine, washing, extracts to obtain Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines;
(3) by 10 grams of step (2) products therefroms stirring and refluxing 4 hours in 10 ml acetic anhydride at 145 ℃, extraction, dry, except desolventizing obtains 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxaline;
(4) 3.04 grams of the products of step (3) gained are dissolved in 50 milliliters of dry dichloromethane solvents, at 0 ℃, add 2.0 grams of metachloroperbenzoic acids, at 25 ℃, react 8 hours; Reacted rear extraction, dry, except desolventizing, after column chromatography purification, obtain product Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxaline;
(5) by 3.2 grams of methanol aqueous solutions that are dissolved in the 80 volume % of 50 milliliters of the product of step (4) gained, add 0.55 gram of potassium carbonate powder at 0 ℃, at 25 ℃, stirring reaction is 3 hours; After having reacted, except desolventizing, filter, washing, dry air, obtains Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline;
(6) 1 gram of the product of step (5) gained is dissolved in to 24 milliliter of 60 volume % aqueous ethanolic solution, at 80 ℃, add 10 grams of V-Brite Bs, at 80 ℃, react 1.5 hours, except desolventizing, washing, extraction, dry, after column chromatography, obtain 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines.
Described quinoxaline compound is the application in target animals internal metabolism residue detection at mequindox; Described quinoxaline compound can be used as mequindox at the residual marker of target animals internal metabolism.
The application of described quinoxaline compound mequindox residue detection in animal derived food; Described quinoxaline compound can be used as residual standard substance or the reference substance of mequindox in animal derived food.
Compared with prior art, the present invention has following beneficial effect:
1, raw material is cheap and easy to get: mequindox, V-Brite B, potassium acetate, potassiumiodide, salt of wormwood, DMF etc. are conventional raw material and reagent;
2, reaction conditions is gentle, under relatively mild condition, reacts, and reaction yield is high;
3, the 1-of gained oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxaline is that people are to the pharmacology of mequindox, toxicity, and the research such as residual provides standard substance or reference substance in food animal body, facilitate the correlative studys such as pharmacokinetics in animal body of mequindox and elimination regularity thereof, can illustrate mequindox pharmacokinetics, metabolism and elimination regularity in animal body.
Accompanying drawing explanation
Fig. 1 is preparation method's of the present invention synthetic route chart;
Fig. 2 is gained 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines
1h-NMR figure;
Fig. 3 is the mass spectrum of gained 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines.
Embodiment
Below in conjunction with embodiment, further explain the present invention, but embodiment does not limit in any form to the present invention.
25 grams of mequindoxes are dissolved in 200 ml methanol, under agitation condition, at 0 ℃, add 3 grams of sodium borohydrides (adding in 20 minutes), then control temperature of reaction and under 30 ℃ of conditions, continue reaction 8 hours, TLC point plate is followed the tracks of reaction and is finished.Then solid collected by filtration precipitate obtains product 1,4-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, filtrate is concentrated into 50 milliliters, 0 ℃ of placement, refilter collection precipitate, after merging, be total to obtain 14 grams of Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl) ,-quinoxaline products, productive rate 56%;
By 3.1 gram 1,4-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, 50 milliliters of pyridines, 1.6 grams of diacetyl oxides in 0 ℃ of mixing, then under room temperature, continue to stir 5 hours, be evaporated to 5-10 milliliter, then add 50 milliliters of frozen water, then with 50 milliliters of ethyl acetate extractions three times, merge organic phase, dry, removal of solvent under reduced pressure, obtain 3.7 grams of Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines, productive rate 99%;
By 10 gram 1,4-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines and 10 ml acetic anhydride mixing solutionss stirring and refluxing 4 hours at 145 ℃, add 50 ml waters, then with 50 milliliters of ethyl acetate extractions three times, dry, revolve and steam desolventizing and obtain 11.5 grams of 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxalines, productive rate 99%;
3.04 grams of 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl) ,-quinoxalines are dissolved in 50 milliliters of dry dichloromethane solvents, 0 ℃ adds 2.0 grams of metachloroperbenzoic acids (adding in 5 minutes), under room temperature, continue reaction 8 hours, organic phase is used respectively saturated solution of sodium carbonate, water, saturated common salt water washing, be spin-dried for except desolventizing, fluid column chromatography purification is separated obtains 1,4 dioxies-2-(1-ethoxycarbonyl-ethyl)-3.1 grams of 4-ethoxycarbonylmethyl group-quinoxalines (elutriant is sherwood oil: ethyl acetate=2:1), and productive rate 97%;
By 3.2 gram 1,4 dioxies-2-(1-ethoxycarbonyl-ethyl)-4-ethoxycarbonylmethyl group-quinoxalines are dissolved in the methanol aqueous solution of the 80 volume % of 50 milliliters, 0 ℃ adds 0.55 gram of potassium carbonate powder, and stirring at room, after 3 hours, is revolved to steam and removed methyl alcohol, filter, 1 milliliter of cold water washing 3 times for filter cake, dry air, obtains 1,4-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline sterling is 2.1 grams, productive rate 89%;
By 1.0 gram 1,4-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxalines are dissolved in 24 milliliter of 60 volume % aqueous ethanolic solution, then add 10 grams of V-Brite Bs (adding in 30 minutes) at 80 ℃, then in 80 ℃, continue reaction 1.5 hours, reaction finishes rear decompression and removes ethanol, then add 20 ml waters, with 20 milliliters of EtOAc extractions three times, merge organic phase, dry, removal of solvent under reduced pressure, column chromatography (sherwood oil: ethyl acetate=1:1) obtain 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines, productive rate 64%.
embodiment 2
25 grams of mequindoxes are dissolved in 100 milliliter of 95 volume % aqueous ethanolic solution, under agitation condition, at 10 ℃, add 5 grams of POTASSIUM BOROHYDRIDE (adding in 20 minutes), then control temperature of reaction and under 20 ℃ of conditions, continue reaction 1 hour, TLC point plate is followed the tracks of reaction and is finished.Then solid collected by filtration precipitate obtains product 1,4-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, filtrate is concentrated into 50 milliliters, 0 ℃ of placement, refilter collection precipitate, after merging, be total to obtain 15.75 grams of Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl) ,-quinoxaline products, productive rate 63%;
By 3.1 gram 1,4-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, 10 milliliters of pyridines, 5 grams of diacetyl oxides in 0 ℃ of mixing, then 30 ℃ are continued to stir 1 hour, are evaporated to 5-10 milliliter, then add 50 ml waters, then with 50 milliliters of ethyl acetate extractions three times, merge organic phase, dry, removal of solvent under reduced pressure, obtain 3.36 grams of Isosorbide-5-Nitrae-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines, productive rate 89%;
By 10 gram 1,4-dioxy-2-(1-ethoxycarbonyl-oxygen ethyl)-3-methyl-quinoxalines and 5 ml acetic anhydride mixing solutionss stirring and refluxing 10 hours at 100 ℃, add 50 ml waters, then with 50 milliliters of ethyl acetate extractions three times, dry, revolve and steam desolventizing and obtain 7.1 grams of 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl)-quinoxalines, productive rate 62%;
3.04 grams of 1-oxygen-2-(1-ethoxycarbonyl-oxygen ethyl)-3-(1-ethoxycarbonyl-oxygen methyl) ,-quinoxalines are dissolved in 100 milliliters of dry dichloromethane solvents, the hydrogen peroxide that adds 10 milliliter 30% under room temperature, 30 ℃ are continued reaction 24 hours, organic phase is used respectively saturated solution of sodium carbonate, water, saturated common salt water washing, be spin-dried for except desolventizing, fluid column chromatography purification is separated obtains 1,4 dioxies-2-(1-ethoxycarbonyl-ethyl)-1.76 grams of 4-ethoxycarbonylmethyl group-quinoxalines (elutriant is sherwood oil: ethyl acetate=2:1), and productive rate 55%;
By 3.2 gram 1,4 dioxies-2-(1-ethoxycarbonyl-ethyl)-4-ethoxycarbonylmethyl group-quinoxalines are dissolved in the 95 volume % aqueous ethanolic solutions of 200 milliliters, 10 ℃ add 0.33 gram of powdered sodium carbonate, and stirring at room, after 8 hours, is revolved to steam and removed ethanol, filter, 1 milliliter of cold water washing 3 times for filter cake, dry air, obtains 1,4-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline sterling is 1.8 grams, productive rate 78%;
By 1.0 gram 1,4-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxalines are dissolved in 25 milliliter of 60 volume % aqueous ethanolic solution, then add 50 grams of V-Brite Bs (adding in 30 minutes) at 23 ℃, then in 23 ℃, continue reaction 10 hours, reaction finishes rear decompression and removes ethanol, then add 20 ml waters, with 20 milliliters of EtOAc extractions three times, merge organic phase, dry, removal of solvent under reduced pressure, column chromatography (sherwood oil: ethyl acetate=1:1) obtain 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines, productive rate 59%.
The spectral data of gained 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines:
1H-NMR：（600MHz，DMSO）：δ=?8.06?(m,?2H),?7.82?(m,?2H),?5.46?(m,?1H),?5.27?(m,?1H),?4.98-4.90?(m,?2H),?1.55?(d,?J?=?5.6Hz,?3H)。
13C-NMR：（400MHz，CDCl3）：δ=?158.1,?153.5,?142.9,?142.0,?130.7,?130.1,?129.6,?129.3,?96.1,?76.0,?19.3
LRMS（ESI）：203.16?(M-H
2O+H
+)。
embodiment 3
The oral mequindox of health pig, after 12 hours, is butchered, and adopts lung tissue, and through Mechanical Crushing, organic solvent extraction 3 times, nitrogen dries up, and adds moving phase and makes sample solution; Separately get the lung tissue of not administration health pig and make blank by preceding method; Get compound (I) and add the reference substance solution that moving phase is made 1mg/mL.
High performance liquid chromatograph, U.S. Dai An company; Chromatographic condition: Hypersil BDS C
18chromatographic column, 250 mm * 5, mm * 4.6 μ m, column temperature: 30 ℃; Moving phase: methyl alcohol (B)/water (containing 0.01% formic acid) (A), gradient elution: 0～40 min, 20%～35% B; 40～45 min, 35%～60% B; 45～57 min, 60% B; 57～60 min, 60%～20% B; 60～65 min, 20% B; Flow velocity: 1 mL/min, detects wavelength: 241 nm.
Compound (I) retention time 32.15min, in sample solution there is peak in 32.09min, blank sample is at 30min-35min Wei Chu peak.
embodiment 4
Healthy chicken intramuscular injection mequindox is after 4 hours, blood-sample withdrawal, and organic solvent extraction 3 times, nitrogen dries up, and adds moving phase and makes sample solution; Separately get the not blood sample of administration healthy chicken and make blank by preceding method; Get compound (I) and add the reference substance solution that moving phase is made 1mg/mL.
High performance liquid chromatograph, U.S. Dai An company; Chromatographic condition: Hypersil BDS C
18chromatographic column, 250 mm * 5, mm * 4.6 μ m, column temperature: 30 ℃; Moving phase: methyl alcohol (B)/water (containing 0.01% formic acid) (A), gradient elution: 0～40 min, 20%～35% B; 40～45 min, 35%～60% B; 45～57 min, 60% B; 57～60 min, 60%～20% B; 60～65 min, 20% B; Flow velocity: 1 mL/min, detects wavelength: 241 nm.Compound (I) retention time 32.15min, in sample solution there is peak in 31.96min, blank sample is at 30min-35min Wei Chu peak.
Claims (10)
1. a quinoxaline compound, the chemical name that it is characterized in that described quinoxaline compound is 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxaline, has structure as shown in formula I:
（Ⅰ）。
2. a preparation method for quinoxaline compound described in claim 1, is characterized in that comprising the steps:
(1) in reactor, add respectively mequindox, solvent, at 0 ~ 10 ℃, add reductive agent to mix, stirring reaction at 20 ~ 30 ℃, filters, and obtains product Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines;
(2) step (1) products therefrom, diacetyl oxide, pyridine are mixed at 0 ~ 10 ℃ to stirring reaction at 10 ~ 100 ℃; After having reacted, except desolventizing, washing, extracts to obtain product Isosorbide-5-Nitrae-dioxy-2-(1-acetoxyl group ethyl)-3-methyl-quinoxaline;
(3) step (2) products therefrom is reacted in diacetyl oxide at 100 ~ 150 ℃, obtain product 1-oxygen-2-(1-acetoxyl group ethyl)-3-(1-acetoxy-methyl)-quinoxalines;
(4) product of step (3) gained is mixed at 0 ~ 10 ℃ to stirring reaction at 10 ~ 100 ℃ with solvent and oxygenant; Reacted rear extraction, dry, except desolventizing, after column chromatography purification, obtain product Isosorbide-5-Nitrae-dioxy-2-(1-acetoxyl group ethyl)-3-(1-acetoxy-methyl)-quinoxaline;
(5) product of step (4) gained is mixed at 0 ~ 10 ℃ to stirring reaction at 20 ~ 30 ℃ with alkali, solvent; After having reacted, except desolventizing, filter, washing, dry air, obtains product Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline;
(6) by the product of step (5) gained and solvent, reductive agent hybrid reaction at 0 ~ 110 ℃, after column chromatography purification product 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines;
Described in step (1), reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
Reductive agent described in step (6) is a kind of in V-Brite B, iron powder and hydrochloric acid, zinc powder and hydrochloric acid, hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE or sodium cyanoborohydride.
3. preparation method as claimed in claim 2, is characterized in that described in step (1), solvent is the mixture of alcohol or alcohol and water, and the reaction times is 0.5 ~ 10 hour; The ratio of described mequindox, reductive agent, solvent is 25g:3 ~ 6g:50 ~ 200mL.
4. preparation method as claimed in claim 2, is characterized in that described in step (2), stirring reaction temperature is 20 ~ 30 ℃, and the reaction times is 0.5 ~ 10 hour; Described Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines, diacetyl oxide, pyridine ratio are 3g:1.5 ~ 5g:10 ~ 100mL.
5. preparation method as claimed in claim 2, is characterized in that described in step (3) that the reaction times is 1 ~ 10 hour; The ratio of described Isosorbide-5-Nitrae-dioxy-2-(1-acetoxyl group ethyl)-3-methyl-quinoxalines, diacetyl oxide is 10g:5 ~ 50mL.
6. preparation method as claimed in claim 2, it is characterized in that described in step (4), stirring reaction temperature is 20 ~ 30 ℃, reaction oxygenant is oxygen, air, ozone, hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide, metachloroperbenzoic acid, potassium hydrogen persulfate, potassium permanganate; Described solvent is methylene dichloride; Reaction times is 0.5 ~ 24 hour; The mol ratio of described 1-oxygen-2-(1-acetoxyl group ethyl)-3-(1-acetoxy-methyl)-quinoxalines and oxygenant is 1:1 ~ 10.
7. preparation method as claimed in claim 2, is characterized in that the ratio of Isosorbide-5-Nitrae-dioxy-2-described in step (5) (1-acetoxyl group ethyl)-3-acetoxy-methyl-quinoxalines and alkali, solvent is 0.01mol:0.0005 ~ 0.005mol:50 ~ 200mL; Described alkali is salt of wormwood, sodium carbonate, and solvent is the mixed solvent of methyl alcohol, ethanol, methyl alcohol and water or ethanol and water.
8. preparation method as claimed in claim 2, is characterized in that described in step (6), temperature of reaction is 0 ~ 80 ℃; Reaction times is 0.5 ~ 10 hour; Solvent is one or more the mixture in water, methyl alcohol, ethanol, and the ratio of described Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxalines, reductive agent is 10g:10 ~ 100g.
9. the preparation method of quinoxaline compound as claimed in claim 2, is characterized in that comprising the steps:
(1) in reactor, add respectively 25 grams of mequindoxes, 100 milliliter of 95 volume % aqueous ethanolic solution, at 10 ℃, add 5 grams of sodium borohydrides, at 20 ℃, stirring reaction is 1 hour, has reacted rear filtration, obtain product Isosorbide-5-Nitrae-dioxy-3-methyl-2-(1-hydroxyethyl)-quinoxalines;
(2) 50 milliliters of 3.1 grams of step (1) products therefroms, 1.6 grams of diacetyl oxides, pyridine are mixed at 0 ℃, then at 25 ℃, react 5 hours; After having reacted, remove pyridine, washing, extracts to obtain product Isosorbide-5-Nitrae-dioxy-2-(1-acetoxyl group ethyl)-3-methyl-quinoxalines;
(3) by 10 grams of step (2) products therefroms stirring and refluxing 4 hours in 10 ml acetic anhydride at 145 ℃, extraction, dry, except desolventizing obtains product 1-oxygen-2-(1-acetoxyl group ethyl)-3-(1-acetoxy-methyl)-quinoxaline;
(4) 3.04 grams of the products of step (3) gained are dissolved in 50 milliliters of dry dichloromethane solvents, at 0 ℃, add 2.0 grams of metachloroperbenzoic acids, at 25 ℃, react 8 hours; Reacted rear extraction, dry, except desolventizing, after column chromatography purification, obtain product Isosorbide-5-Nitrae-dioxy-2-(1-acetoxyl group ethyl)-3-(1-acetoxy-methyl)-quinoxaline;
(5) by 3.2 grams of methanol aqueous solutions that are dissolved in the 80 volume % of 50 milliliters of the product of step (4) gained, add 0.55 gram of potassium carbonate powder at 0 ℃, at 25 ℃, stirring reaction is 3 hours; After having reacted, except desolventizing, filter, washing, dry air, obtains product Isosorbide-5-Nitrae-dioxy-2-(1-hydroxyethyl)-3-methylol-quinoxaline;
(6) 1 gram of the product of step (5) gained is dissolved in to 24 milliliter of 60 volume % aqueous ethanolic solution, at 80 ℃, add 10 grams of V-Brite Bs, at 80 ℃, react 1.5 hours, except desolventizing, washing, extraction, dry, after column chromatography, obtain product 1-oxygen-2-methylol-3-(1-hydroxyethyl)-quinoxalines.
Described in claim 1 quinoxaline compound at mequindox in target animals internal metabolism residue detection or the application in mequindox residue detection in animal derived food.
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| 刘迎春等.高效液相色谱-电喷雾离子阱飞行时间质谱法鉴定乙酰甲喹及其代谢物.《分析化学》.2010,第38卷(第1期), |
| 高效液相色谱-电喷雾离子阱飞行时间质谱法鉴定乙酰甲喹及其代谢物;刘迎春等;《分析化学》;20100131;第38卷(第1期);第82-86页 * |
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