CN101648917A - Mequindox metabolic product and preparation method and application thereof - Google Patents
Mequindox metabolic product and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a mequindox metabolic product and a preparation method and an application thereof. The mequindox metabolic product is 3-methyl-2-ethanolquinoxalin-1,4-dioxide, the molecular formula is C11H12N2O3 and the structural formula is shown in formula (I). the preparation method of the compound shown in formula (I) comprises the following steps: adopting mequindox as raw material toperform reducing reaction in the presence of solvent while monitoring the end point, and then performing recrystallization to obtain high purity 3-methyl-2-ethanolquinoxalin-1,4-dioxide. The preparation method of the invention has simple operation, low cost and high end product yield; in addition, the purity can reach above 99%, the preparation method of the invention provides a referable synthesis method for similar metabolic compounds of mequindox, and the prepared reduction product mequindox can be used to prepare the standard substance used in the study of mequindox metabolism.
Description
Technical field
The invention belongs to technical field of biochemical industry, be specifically related to a kind of mequindox metabolic product and its production and application.
Background technology
Mequindox (methlacetylquinoxalinediode) is the treatment antimicrobial drug of China's initiative, is the drug of first choice and the specifics of the pig treponema dysentery (pig bloody flux) of treatment serious harm pig industry.By large scale application and clinical observation, prove that this medicine treatment pig treponema dysentery has that consumption is little, instant effect, curative effect height, characteristics such as safe and reliable, with low cost, easy to use, result of treatment is better than the other treatment medicine.This medicine is for oral administration easily to be absorbed, widely distributed, eliminate 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.
The antifungal mechanism of mequindox is suppress bacteria dna (DNA) synthetic.Because of this medication is imitated definitely with cheap, in China's veterinary clinic widespread use.Since 1980, through the large scale application in 4 years, popularization face was extended to most area of 29 provinces in the whole nation.The pig that causes because of this disease is only dead, weightening finish reduces, the feed wastage rate increase the loss that is caused owing to reduced, and economic benefit added up to 6.4 hundred million yuan in 1980 to 1986.But the toxicity of this medicine, in the food animal body residual research less.Metabolism situation is not in animal body also studied report, and a lot of situations are all had little understanding, and does not also have the metabolic in animal body pertinent literature report of mequindox at present.
The animal-derived food veterinary drug residue can cause allergic reaction, bacterial drug resistance, chronic toxicity effect etc.Along with quinoxaline-1, the drug development of 4-dioxy compounds and promote since, its toxic side effect also receives much concern, the toxicity that the olaquindox in the quinoxaline, carbadox, Quinocetone, quinoline match are many, metabolism have had many researchs report with residual.Because the specific toxicity of this class medicine, its use are forbidden or strict restriction: be strong mutagenic compound as carbadox in microorganism and Mammals test macro, pernicious and innocent tumour incidence significantly increases; Olaquindox also has mutagenicity, and the innocent tumour incidence also significantly increases etc.Not good enough in view of carbadox and olaquindox in the security of aquaculture, have the potential potential safety hazard.
The pharmacokinetics and the residual research of most of quinoxaline medicine have obtained carrying out, as, Quinocetone many both at home and abroad to olaquindox, carbadox, quinoline match Deng quinoxaline medicine many reports have been arranged, but the correlative study that China has a veterinary drug mequindox of independent intellectual property right is still belonged to blank.The pharmacokinetics of mequindox, metabolism and residually do not obtain further investigation as yet be not also relevant for the report of residual marker of mequindox and maximum residue limit(MRL).
Cause the problem of its content severe overweight in animal body at a large amount of abuses of quinoxaline medicine additive, the off-drug period and residual the limiting the quantity of of formulating all medicines of quinoxaline are very urgent, but the formulation of off-drug period should be worked out according to the residual marker of this medicine and the residual eliminating rule of former medicine, so the structure of the intravital meta-bolites of each medicine infers that it is to formulate residual prerequisite prerequisite of limiting the quantity of that evaluation and pure product synthesize in the quinoxaline.The pharmacokinetics and the residual research of most of quinoxaline medicine have obtained carrying out, but the correlative study that China has a veterinary drug mequindox of independent intellectual property right is still belonged to blank.
At present domestic detection technique to mequindox still rests on the detection to former medicine, mequindox pharmacokinetics and metabolism is residual does not obtain further investigation as yet, also not relevant for the report of residual marker of mequindox and maximum residue limit(MRL).Along with the raising of international standard, the internationalization of China's trade, this detection technique can not meet the demands, and in line with international standards, China is necessary to strengthen the research dynamics to mequindox metabolic product.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of primary metabolite of mequindox is provided.
Another object of the present invention is to provide the preparation method of above-mentioned mequindox metabolic product.
Another object of the present invention is to provide above-mentioned mequindox metabolic product in the application of conduct to the standard substance in the various researchs of mequindox.
Above-mentioned purpose of the present invention is achieved by following scheme:
A kind of mequindox metabolic product, its chemical name are 3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide, and molecular formula is C
11H
12N
2O
3, molecular weight is 220.21, its chemical structural formula is suc as formula shown in (I):
The above-mentioned 3-methyl of a kind of preparation-2-ethanol based quinoxaline-1, the method of 4-dioxide, this method is to be raw material with the mequindox, in the presence of solvent, carry out reduction reaction, mequindox is reducing carbonyl under the effect of reductive agent, monitor reaction end simultaneously, obtain highly purified 3-methyl-2-ethanol based quinoxaline-1,4-dioxide thereby then reaction product is carried out recrystallization.
The reaction equation of above-mentioned reduction reaction is as follows:
Reduction reaction all is to carry out under the solvent condition usually, and among the above-mentioned preparation method, the solvent of reduction reaction is a reagent commonly used in the reduction reaction, as any one or more than one the mixed solvent in water, methyl alcohol, ethyl acetate or the acetonitrile etc.
In the above-mentioned reduction reaction, can adopt reductive agent commonly used that mequindox is carried out reduction reaction, as being reduction reaction, basic metal Bu Weierte-Blang (Bouvealt-Blanc) method reaction of reductive agent with hydrogen, being the reduction reaction of reductive agent, being the reduction reaction (lithium aluminum hydride, sodium borohydride, POTASSIUM BOROHYDRIDE etc.) of reductive agent with the inorganic hydride, being the reduction reaction of reductive agent, being the reduction reaction of reductive agent, being the reduction reaction etc. of reductive agent with the V-Brite B with the imide with the diboron hexahydride with the sodium amalgam; Mequindox and reductive agent can adopt the mol ratio of (4: 1)～(16: 1) to react.
The temperature of reaction of above-mentioned reduction reaction is 10～80 ℃, preferred 30～40 ℃.
In the above-mentioned reduction reaction, carry out analyzing and testing by timing sampling and to institute's sample thief, thus monitoring reduction reaction terminal point; Described timing sampling can adopt every 5 minutes timing samplings, and described analysing and detecting method can adopt stratographic analysis commonly used, analyzes detection method as high performance liquid chromatography, thin-layer chromatography etc.; Described monitoring reduction reaction terminal point is meant snab sample is carried out analyzing and testing that the mequindox chromatographic peak disappears in institute's test sample product, illustrates that mequindox is reduced thoroughly, is reaction end this moment.
After above-mentioned reduction reaction finishes, before reaction product is carried out recrystallization, also can add step organic solvent extraction reaction again, make end product 3-methyl-2-ethanol based quinoxaline-1, the purity of 4-dioxide is higher; Described organic solvent extraction can adopt organic solvent commonly used such as ethyl acetate, trichloromethane, methylene dichloride or acetonitrile, after the extraction several times, use the distilled water wash organic phase, adopt siccative commonly used such as anhydrous sodium sulphate, Calcium Chloride Powder Anhydrous or anhydrous magnesium sulfate that organic phase is carried out drying then, evaporated under reduced pressure then, obtain 3-methyl-2-ethanol based quinoxaline-1, the thick product of 4-dioxide.
To above-mentioned 3-methyl-2-ethanol based quinoxaline-1, the thick product of 4-dioxide carries out recrystallization purifying, the principle of recrystallization is to change variant according to the solubility with temperature of target compound in certain solvent, solubleness is big under comparatively high temps, and solubleness is little when reducing temperature, purify thereby realize separating, conventional way is adopted in recrystallization operation of the present invention: earlier with 3-methyl-2-ethanol based quinoxaline-1, the thick product of 4-dioxide is dissolved in the organic solvent with comparatively high temps, the processing of lowering the temperature after the dissolving, have crystal and separate out this moment, suction filtration dissolves in the gained crystal in the organic solvent of above-mentioned comparatively high temps once more then, and cooling is handled again, separate out, suction filtration, so behind the periodic crystallisation, suction filtration, drying just can obtain faint yellow needle-like crystal thing, are end product 3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide, its structural formula is suc as formula shown in (I).
The above-mentioned organic solvent that is used for recrystallization can be selected 95 volume % ethanol, trichloromethane, methylene dichloride, acetonitrile, ethyl acetate, Virahol or the methyl alcohol etc. used always.
Synthetic 3-methyl of the present invention-2-ethanol based quinoxaline-1, the 4-dioxide detects by detection meanss such as UV scanning, high performance liquid phase and mass spectrums, and with the 3-methyl-2-ethanol based quinoxaline-1 of internal metabolism, the 4-dioxide compares, the result is identical, prove synthetic 3-methyl of the present invention-2-ethanol based quinoxaline-1 thus, the 4-dioxide is the meta-bolites of mequindox, can be used as the standard substance in the researchs such as intravital pharmacokinetics of pharmacological research, toxicological study, animal that people carry out mequindox and residual eliminating rule.
Adopt method for preparing gained 3-methyl-2-ethanol based quinoxaline-1, its purity of 4-dioxide can reach 99%, can be used as standard substance fully, for people to the pharmacological research of mequindox, toxicological study and in the food animal body residual research approach easily is provided, the meta-bolites that also can be used as mequindox carries out a series of test, as toxicity test, the test of pesticide effectiveness even be used for actual production.
Compared with prior art, the present invention has following beneficial effect:
1. 3-methyl of the present invention-2-ethanol based quinoxaline-1,4-dioxide can be used as the residual marker of mequindox as the super meta-bolites of mequindox, are used for the formulation of mequindox off-drug period;
2. 3-methyl of the present invention-2-ethanol based quinoxaline-1, the preparation method of 4-dioxide, its operation is succinct, with low cost, and in the preparation method, adopt stratographic analysis control reaction end, and the organic solvent extraction reaction product, and crude product is carried out recrystallization purify, the combination in these three steps not only makes the output height of end product, and has guaranteed that the purity of final product can reach more than 99%;
3. 3-methyl of the present invention-2-ethanol based quinoxaline-1, the preparation method of 4-dioxide is for the similar reducing compound of mequindox provides the synthetic method that a cover can reference;
4. the 3-methyl-2-ethanol based quinoxaline-1 that obtains by preparation method of the present invention, the 4-dioxide is because of its purity height, standard substance when can be used as the research of pharmacological research, toxicological study, pharmacokinetics in animal body and residual rule thereof etc. to mequindox, for the research of carrying out mequindox and illustrate mequindox pharmacokinetics, metabolism and residual eliminating rule in animal body and lay the first stone, can be used for studying the antimicrobial effect research of quinoxaline compound analogue in addition.
Description of drawings
Fig. 1 prepares gained 3-methyl-2-ethanol based quinoxaline-1, the uv absorption spectra of 4-dioxide for embodiment;
Fig. 2 is the uv absorption spectra of mequindox interior metabolism product (3-methyl-2-ethanol based quinoxaline-1,4-dioxide);
Fig. 3 prepares gained 3-methyl-2-ethanol based quinoxaline-1 for embodiment, the one-level mass spectrum of 4-dioxide;
Fig. 4 prepares gained 3-methyl-2-ethanol based quinoxaline-1 for embodiment, the 4-dioxide second order ms figure;
Fig. 5 is the one-level mass spectrum of mequindox interior metabolism product (3-methyl-2-ethanol based quinoxaline-1,4-dioxide);
Fig. 6 is the second order ms figure of mequindox interior metabolism product (3-methyl-2-ethanol based quinoxaline-1,4-dioxide).
Embodiment
The present invention will be further explained below in conjunction with specific embodiment, but specific embodiment is not done any qualification to the present invention.
Present embodiment is raw material with the mequindox, V-Brite B is a reductive agent, carry out reduction reaction, and by high performance liquid chromatography monitoring reaction end, thereby then reaction product is carried out recrystallization and obtain highly purified 3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide, its preparation method is specific as follows:
(1) high-efficient liquid phase chromatogram determining condition determines
Chromatographic column: Symmetry C18 (250mm * 4.6mm, 5 μ m), U.S. Waters company;
Guard column: C18,4.6mm * 3.0mm (i.d), U.S. Phenomenex company;
Detect wavelength: 240nm;
Column temperature: 30 ℃;
Moving phase: methyl alcohol-deionized water (40/60, V/V);
Waters Alliance2695 highly effective liquid phase chromatographic system, 2487 UV-detector.
(2) take by weighing the mequindox of 2.18g, stir, make it to be dissolved in the 200mL methyl alcohol, the magnetic stirring apparatus high-speed stirring, slowly drip 0.5mol/L sodium borohydride aqueous solution (keeping about 10mL/min),, carry out the high-performance liquid chromatogram determination analysis every 5 minutes timing samplings, high-efficient liquid phase chromatogram determining condition is as implied above, and the entire reaction temperature is controlled at 30 ℃; Monitoring is reacted to the mequindox chromatographic peak and is disappeared, decompression is evaporated near doing with reaction solution, product in ethyl acetate (50mL) the extractive reaction liquid, extract three times, merge organic phase, the distilled water wash organic phase, and use anhydrous magnesium sulfate drying, the evaporated under reduced pressure ethyl acetate obtains the tawny crude product, and is standby;
(3) above-mentioned tawny crude product all is dissolved in 60 ℃, 50mL 95% ethanol, places 4 ℃ of refrigerator overnight, have yellow needle-like crystal to settle out suction filtration; Yellow needle-like crystal is dissolved in 60 ℃, 50mL95% ethanol once more, and so periodic crystallisation is 3 times, suction filtration, and the vacuum drying oven inner drying obtains faint yellow needle-like crystal 1.527g, and the rate of recovery is 70.04%, and purity is 99%.
The uv absorption spectra of above-mentioned faint yellow needle-like crystal as shown in Figure 1, its mass spectrum is shown in Fig. 3 and 4, by with this three width of cloth figure and mequindox interior metabolism product (3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide) uv absorption spectra (Fig. 2) and mass spectrum (Fig. 5 and 6) contrast, the uv-absorbing spectral line and mequindox interior metabolism product (the 3-methyl-2-ethanol based quinoxaline-1 of the faint yellow needle-like crystal of present embodiment preparation as can be seen, the 4-dioxide) uv-absorbing spectral line basically identical, the mass spectrum curve of the faint yellow needle-like crystal of present embodiment preparation also with mequindox interior metabolism product (3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide) mass spectrum curve unanimity, illustrate that thus it is exactly 3-methyl-2-ethanol based quinoxaline-1 that present embodiment prepares the faint yellow needle-like crystal of gained, the 4-dioxide.
Claims (9)
1, a kind of mequindox metabolic product, its chemical name are 3-methyl-2-ethanol based quinoxaline-1, the 4-dioxide, and molecular formula is C
11H
12N
2O
3, its chemical structural formula is suc as formula shown in (I):
2, a kind of method for preparing the described mequindox metabolic product of claim 1, it is characterized in that this method is is raw material with the mequindox, in the presence of solvent, carry out reduction reaction, and the monitoring reaction end, thereby then reaction product is carried out compound shown in the recrystallization acquisition formula (I).
3,, it is characterized in that described solvent is any one or more than one the mixed solvent in water, methyl alcohol, ethyl acetate or the acetonitrile according to the described preparation method of claim 2.
4,, it is characterized in that the reductive agent in the described reduction reaction is hydrogen, basic metal, sodium amalgam, lithium aluminum hydride, sodium borohydride, POTASSIUM BOROHYDRIDE, diboron hexahydride, imide or V-Brite B according to the described preparation method of claim 2.
5, according to the described preparation method of claim 2, the reaction mol ratio that it is characterized in that the reductive agent in described mequindox and the reduction reaction is 4: 1～16: 1.
6, according to the described preparation method of claim 2, the temperature of reaction that it is characterized in that described reduction reaction is 10～80 ℃.
7,, it is characterized in that described reduction reaction adopts high performance liquid chromatography or tlc monitoring reaction end according to the described preparation method of claim 2.
8,, it is characterized in that the product of described reduction reaction carries out the organic solvent extraction reaction earlier before recrystallization according to the described preparation method of claim 2.
9, the application of the described mequindox metabolic product of a kind of claim 1 is characterized in that being applied as research mequindox standard substance.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914071A (en) * | 2010-07-16 | 2010-12-15 | 中国农业大学 | Preparation method of 2-methyquinoxaline-1,4-dioxide |
| CN102070540A (en) * | 2010-12-31 | 2011-05-25 | 广州自远生物科技有限公司 | 1-oxygen-2-(1-ethoxy)-3-methyl-quinoxaline, and preparation method and application thereof |
| CN106568866A (en) * | 2016-11-10 | 2017-04-19 | 山东省海洋资源与环境研究院 | Measuring method of desoxym equindox, 3-metyl-2-acetyl-quinoxaline and MQCA in trepang |
| CN109164185A (en) * | 2018-10-10 | 2019-01-08 | 福建省农业科学院农业质量标准与检测技术研究所 | The method of mequindox and its major metabolite in HPLC Simultaneous Determination aquatic products |
-
2009
- 2009-07-14 CN CN2009100411188A patent/CN101648917B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914071A (en) * | 2010-07-16 | 2010-12-15 | 中国农业大学 | Preparation method of 2-methyquinoxaline-1,4-dioxide |
| CN101914071B (en) * | 2010-07-16 | 2015-04-15 | 中国农业大学 | Preparation method of 2-methyquinoxaline-1,4-dioxide |
| CN102070540A (en) * | 2010-12-31 | 2011-05-25 | 广州自远生物科技有限公司 | 1-oxygen-2-(1-ethoxy)-3-methyl-quinoxaline, and preparation method and application thereof |
| CN102070540B (en) * | 2010-12-31 | 2013-11-20 | 广州自远生物科技有限公司 | 1-oxygen-2-(1-ethoxy)-3-methyl-quinoxaline, and preparation method and application thereof |
| CN106568866A (en) * | 2016-11-10 | 2017-04-19 | 山东省海洋资源与环境研究院 | Measuring method of desoxym equindox, 3-metyl-2-acetyl-quinoxaline and MQCA in trepang |
| CN109164185A (en) * | 2018-10-10 | 2019-01-08 | 福建省农业科学院农业质量标准与检测技术研究所 | The method of mequindox and its major metabolite in HPLC Simultaneous Determination aquatic products |
| CN109164185B (en) * | 2018-10-10 | 2021-08-10 | 福建省农业科学院农业质量标准与检测技术研究所 | Method for simultaneously and quantitatively determining mequindox and main metabolites thereof in aquatic products by HPLC |
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