CN103420926B - The chemical synthesis process of four kinds of metabolites of quinocetone - Google Patents
The chemical synthesis process of four kinds of metabolites of quinocetone Download PDFInfo
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- CN103420926B CN103420926B CN201310225015.3A CN201310225015A CN103420926B CN 103420926 B CN103420926 B CN 103420926B CN 201310225015 A CN201310225015 A CN 201310225015A CN 103420926 B CN103420926 B CN 103420926B
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Abstract
The present invention relates to four kinds of major metabolite desoxyquinocetones of quinocetone, desoxyquinocetone side chain carbonyl reduction product, N1-deoxidation quinocetone and N4The synthetic method of-deoxidation quinocetone side chain carbonyl reduction product. Desoxyquinocetone synthetic be with sodium dithionite to mequindox deoxidation, generate the de-dioxy mequindox of intermediate, then with benzaldehyde, obtain desoxyquinocetone. Then with sodium borohydride, its side chain carbonyl is reduced, obtain desoxyquinocetone side chain carbonyl reduction product. With Trimethyl phosphite, to mequindox, selective deoxidation generates N1-deoxidation mequindox, with benzaldehyde, obtains N1-deoxidation quinocetone. With suitable amine, to mequindox, selective deoxidation generates N1-deoxidation mequindox, with benzaldehyde, obtains N1-deoxidation quinocetone, the carbonyl reduction with sodium borohydride to its side chain, obtains N4-deoxidation quinocetone side chain carbonyl reduction product.
Description
Technical field
The invention belongs to veterinary drug synthesis technical field, be specifically related to the synthetic method of four kinds of metabolins of quinoxaline medicine, describedMetabolin relates to desoxyquinocetone (Q1), desoxyquinocetone side chain carbonyl reduction product (Q2), N1-deoxidation quinocetone (Q3) andN4-deoxidation quinocetone side chain carbonyl reduction product (Q4.
Background technology
The chemical name of quinocetone (quinocetone, QCT) is 3-methyl-2-cinnamoyl-quinoxalines-N1，N4-dioxide, isThe new veterinary drug of country's one class by the research and development of Lanzhou herding veterinary drug research institute of the Chinese Academy of Agricultural Sciences in 2003, as a kind of novel Kui EvilQuinoline class antivirus somatotropic agent, has been widely used in veterinary clinic. But it is certain clinical to there are some researches show that quinoxaline medicine hasToxicity, main manifestations is liver renal toxicity, Adrenal Injury, aldosterone and serum ion content etc. Dui Kui Evil in recent yearsThe further investigation of quinoline class drug toxicology also shows that it has potential mutagenesis, teratogenesis and carcinogenesis. In recent years studies have reported thatThe cytotoxicity that quinocetone has is higher than olaquindox and carbadox (Chenetal., 2009), and human liver tumor cell (HepG2) is shownReveal genetoxic (Jinetal., 2009). But owing to lacking the drug safety evaluation about quinocetone of system, so far without residualStay the foodsafety standards such as target tissue, residual mark and off-drug period. For the theory about quinocetone safety evaluatio is providedFoundation, is necessary quinocetone to carry out metabolism and the residual research of system, illustrates its elimination regularity research, determines that it is residualTarget tissue and residual marker, formulate the off-drug period. The standard items of preparing quinocetone major metabolite can be for disclosing quinocetoneThe metabolin that toxicity is relevant props up for the residual quantity of the quinocetone correlative metabolites in quantitative assay edible animal tissue provides simultaneouslyHold, illustrate quinocetone metabolic process and elimination regularity thereof in animal body, thereby for the day of formulating quinocetone allowing intake(ADI), MRL (MRL) and off-drug period lay the foundation.
Had some reports, the yellow tinkling of pieces of jade of Hua Zhong Agriculture University to the research of quinocetone metabolite identification in animal body early stageProfit wait and from pig chicken tissue, found two metabolite desoxyquinocetones and 3-methyl-Oxoquinoxaline-2-carboxylic acids (Huangetal.,2005). Shanghai veterinary institute Zhang Lifang studies and shows, the metabolism of quinocetone in chicken body mainly discharged with original shape form, chicken manureIn except there is quinocetone original shape, outside desoxyquinocetone and 3-methyl-Oxoquinoxaline-2-carboxylic acids, also find that there is two new metabolitesN1-deoxidation quinocetone and N4-deoxidation quinocetone (Zhang Lifang, 2006). The research such as Liu Zhaoying finds that quinocetone is at pig, chicken animal bodyInterior main metabolites has following five kinds: 3-methyl-Oxoquinoxaline-2-carboxylic acids (3-methyl-2-Quinoxalinecarboxylicacid,MQCA); Desoxyquinocetone (2-Propen-1-one-1-(3-methyl-2-quinoxalinyl)-3-phenyl-, Q1); De-dioxy quinolineKetenes carbonyl reduction product (2-Quinoxalinemethanol-3-methyl-α-(2-phenylethenyl)-, Q2); N1-deoxidation quinoline alkeneKetone (2-Propen-1-one-1-(3-methyl-4-oxide-2-quinoxalinyl)-3-phenyl-, Q3) and N4-deoxidation quinocetone carbonyl alsoFormer product (2-Quinoxalinemethanol, 3-methyl-α-(2-phenylethenyl)-, 1-oxide, Q4), its possible metabolism wayFootpath (Liu Zhaoying, 2009) as shown in Figure 1.
At present, 3-methyl-Oxoquinoxaline-2-carboxylic acids (MQCA) synthetic relevant have patent literature (CN101016267, andCN101012202). Synthetic to desoxyquinocetone (Q1), Zhang Lifang etc. (Zhang Lifang, 2006) in chicken manure quinocetone andIn the identification research of metabolin, synthesized desoxyquinocetone taking quinocetone as raw material, the method for employing is taking quinocetone as raw material,Use Na2S2O4For reducing agent deoxidation, first result generates three kinds of product: N1-deoxidation quinocetone, N4-deoxidation quinocetone and de-twoOxygen quinocetone, further deoxidation obtains desoxyquinocetone, in literary composition, mentions, and controls reaction condition extremely important, and we are in experimentIn also find that reaction temperature height can cause accessory substance to increase and even can not get product, and the too low product that has a de-oxygen of temperature,Not only productive rate is low to cause desoxyquinocetone synthetic, and accessory substance is many, is unfavorable for purifying. Other three kinds of main metabolites,De-dioxy carbonyl quinocetone side chain carbonyl reduction product (Q2), N1-deoxidation quinocetone (Q3) and N4-deoxidation quinocetone side chain carbonyl alsoThe synthetic bibliographical information that yet there are no of four kinds of metabolites such as former product (Q4).
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, supply raw materials be easy to get, easy and simple to handle, selective good quinocetone fourPlant the synthetic method of major metabolite, can be for the different deoxidation metabolin of synthetic quinoxaline compound supplying method, for deeply grindingThe metabolism in animal body of Jiu quinoxaline medicine and elimination regularity and drug safety evaluation thereof provide technical support.
The technical scheme that realizes the object of the invention is as described below:
Synthetic route of the present invention as shown in Figure 2.
Four kinds of metabolins of quinocetone are desoxyquinocetone, desoxyquinocetone side chain carbonyl reduction product, N1-deoxidation quinocetoneWith the synthetic method of N4-deoxidation quinocetone side chain carbonyl reduction product, it is following steps:
1) desoxyquinocetone is synthetic: taking mequindox as raw material, sodium dithionite reduces to it, obtains de-dioxyMequindox, then carry out condensation with benzaldehyde, obtain desoxyquinocetone;
2) upper step gained desoxyquinocetone is dissolved in to solvent methanol, ethanol, isopropyl alcohol, in carrene or ethyl acetate, chamberUnder temperature, reduce with sodium borohydride or potassium borohydride, obtain desoxyquinocetone side chain carbonyl reduction product;
3) N1-deoxidation quinocetone is synthetic: taking mequindox as raw material, Trimethyl phosphite or triethyl phosphite are reducing agentIt is carried out to selective deoxidation and obtain N1-deoxidation mequindox, then carry out condensation with benzaldehyde, obtain N1-deoxidation quinocetone and produceThing;
4) N4-deoxidation quinocetone carbonyl reduction product is synthetic: taking mequindox as raw material, at suitable replacement amine as azanol,Methylamine, refluxes and obtains N4-deoxidation mequindox with selective deoxidation in dimethylamine or triethylamine solution, then contract with benzaldehydeClose, obtain N4-deoxidation quinocetone, further with sodium borohydride, it is reduced, obtain N4-deoxidation quinocetone side chain carbonylReduzate.
Wherein:
Step 1) in the reducing agent that adopts when synthetic de-dioxy mequindox be sodium dithionite, the throwing of reactant and reducing agentMaterial is than being 1: 1～1: 5, and reaction temperature is 60 DEG C.
Step 2) the middle sodium borohydride that adopts is as reducing agent, and the rate of charge of reactant and reducing agent is 1: 1.5.
Step 3) in N1It is deoxidier, substrate and deoxidier that-deoxidation quinocetone adopts Trimethyl phosphite or triethyl phosphiteThe rate of charge of amount is 1: 1～1: 2.
Step 4) N4In-deoxidation quinocetone side chain carbonyl reduction product, adopt replacement amine to make reducing agent.
Described replacement amine adopts methylamine, dimethylamine or triethylamine, and the rate of charge of substrate and reducing agent is 1: 1～1: 3.
The present invention has the following advantages:
1) synthesis material is cheap and easy to get: raw material used in the present invention and reagent mequindox, sodium dithionite, tricresyl phosphiteMethyl esters or ethyl ester, methylamine, dimethylamine, triethylamine or azanol, sodium borohydride, potassium borohydride etc. is all conventional raw material and reagent,Low price, easily obtains.
2) agents useful for same low toxicity or nontoxic, post processing is simple to operation, and environmental pollution is little.
3) the choosing of deoxygenation in the present invention, target compound productive rate is higher, and purity is good, can meet drug metabolism etc. and grindStudy carefully needs.
Brief description of the drawings
Fig. 1: quinocetone is possible metabolic pathway in pig and chicken body.
Fig. 2: the synthetic route chart that the present invention relates to four kinds of quinocetone main metabolites.
Detailed description of the invention
The present invention will be described below to enumerate specific embodiment. Embodiment, only for the present invention will be further described, does not representProtection scope of the present invention, nonessential amendment and adjustment that other people make according to the present invention, still belong to protection model of the present inventionEnclose.
Embodiment 1:
Get 8.72g (0.04mol) mequindox and be placed in 250mL there-necked flask, add absolute ethyl alcohol 150mL, in 55 DEG CHeating water bath, makes it to dissolve completely. Separately get after 30g sodium dithionite is dissolved in 60mL water and be slowly added dropwise in above-mentioned reaction bulb,Stirring reaction, keeps reaction temperature to be no more than 60 DEG C, after raw material disappears completely, stops reaction. By reacting liquid filtering, filtrateAfter reduced pressure concentration, add ethyl acetate 100mL extraction, in triplicate, combined ethyl acetate layer is with after anhydrous sodium sulfate dryingBe evaporated to 30mL left and right, leave standstill crystallization, filter and obtain de-dioxy mequindox 6.5g (productive rate 88%).
In the 250mL there-necked flask that magnetic agitation is housed, add the de-dioxy mequindox 3.6g (0.02mol) of above-mentioned preparationWith methyl alcohol 50mL, add thermal agitation it is dissolved, after separately getting 2.1mL benzaldehyde and slowly adding solution to stir, then add 2.81gK2CO3Rear back flow reaction, reaction solution is separated out yellow solid, and TLC detects after raw material complete reaction, stops reaction, will be anti-Answer liquid to filter, the solid obtaining is recrystallized and obtains desoxyquinocetone (Q1) 4.0g (productive rate 74%) in ethyl acetate.
Embodiment 2:
Get desoxyquinocetone 1.0g prepared by embodiment 1, be placed in the 100mL that 40mL carrene band magnetic agitation is housedIn there-necked flask, stir and make, after its dissolving, to get 0.33g sodium borohydride, under condition of ice bath, gradation adds in reactant liquor, lamellae(thin-layer chromatography solvent, benzinum: acetone (volume ratio)=4: 1) carried out in point sample monitoring reaction, after raw material disappears completely,In reactant liquor, add saturated ammonium chloride solution 30mL, pour reactant liquor in separatory funnel layering, get organic phase, with anhydrousEvaporated under reduced pressure after dried over sodium sulfate, after adding the heating of 15mL ethyl acetate that it is dissolved, standing recrystallization obtains the de-dioxy of productQuinocetone carbonyl reduction product (Q2) 250mg (productive rate 25%).
Embodiment 3:
Get 8.72g (0.04mol) mequindox and be placed in the there-necked flask of 250mL with magnetic agitation, add isopropyl alcohol 150mL,Separately get 7mL Trimethyl phosphite and be added dropwise in above-mentioned reaction bulb, heating makes it to dissolve completely, and back flow reaction, treats that raw material disappears completelyAfter mistake, stop reaction. By reacting liquid filtering, filtrate, after evaporated under reduced pressure, adds after 30mL acetic acid ethyl dissolution, leaves standstill and analysesGo out crystallization, filter and obtain N1-deoxidation mequindox.
In the 50mL there-necked flask that magnetic agitation is housed, add the N of above-mentioned preparation1-deoxidation mequindox 4.04g (0.02mol)With methyl alcohol 20mL, add thermal agitation it is dissolved, after separately getting 4.5mL benzaldehyde and slowly adding solution to stir, then add 4.5gK2CO3Rear back flow reaction, separates out yellow solid in reaction solution, thin-layer chromatography (TLC) (thin-layer chromatography solvent, benzinum:Acetone (volume ratio)=4: 1) detect after raw material complete reaction, stop reaction, by reacting liquid filtering, the solid 20mL obtainingEthyl acetate heating leaves standstill after making to dissolve, and separates out N1-deoxidation quinocetone (Q3) crystallization 2.8g (productive rate 48%).
Embodiment 4:
Get 10.9g (0.05mol) mequindox and be placed in the there-necked flask of 250mL with magnetic agitation, add 20% methylamineEthanolic solution 50mL, back flow reaction after 4 hours, stop reaction, by reactant liquor after removing ethanol under reduced pressure, impouring 50mL waterIn, add 50mL dichloromethane extraction, in triplicate, combined dichloromethane, and with reduced pressure concentration after anhydrous sodium sulfate drying,Obtain crude product. By crude product through silica gel column chromatography, with benzinum: acetone (v: v=4: 1) wash-out, obtains N4-deoxidation acetylFirst quinoline.
Embodiment 5:
Get 10.9g (0.05mol) mequindox and be placed in the there-necked flask of 250mL with magnetic agitation, add 20% diformazanAmine ethanolic solution 50mL, back flow reaction after 4 hours, stop reaction, by reactant liquor after removing ethanol under reduced pressure, impouring 50mLIn water, add 50mL dichloromethane extraction, in triplicate, combined dichloromethane, and dense with reducing pressure after anhydrous sodium sulfate dryingContracting, obtains crude product. By crude product through silica gel column chromatography, with benzinum: acetone (v: v=4: 1) wash-out, obtains N4-deoxidationMequindox.
Embodiment 6:
Get 10.9g (0.05mol) mequindox and be placed in the there-necked flask of 250mL with magnetic agitation, add 100mL secondAlcohol heating is dissolved it, gets 30mL triethylamine and adds lentamente in reactant liquor, and back flow reaction stops reaction after 4 hours, will be anti-Answer liquid after removing ethanol under reduced pressure, in impouring 50mL water, add 50mL dichloromethane extraction, in triplicate, merge dichloroMethane, and with reduced pressure concentration after anhydrous sodium sulfate drying, obtain crude product. By crude product through silica gel column chromatography, with benzinum:Acetone (v: v=4: 1) wash-out, obtains N4-deoxidation mequindox.
Embodiment 7:
In the 50mL there-necked flask that magnetic agitation is housed, add the N of above-mentioned preparation4-deoxidation mequindox 2.02g (0.01mol)With methyl alcohol 20mL, add thermal agitation it is dissolved, after separately getting 1.5mL benzaldehyde and slowly adding solution to stir, then add 1.5gK2CO3Rear back flow reaction 4 hours, separates out yellow solid in reaction solution, by reacting liquid filtering, and the solid 20mL obtainingEthyl acetate heating leaves standstill after making to dissolve, and separates out N4-deoxidation quinocetone crystallization 1.6g (productive rate 48%). .
Get the N of above-mentioned preparation4-deoxidation quinocetone 1.50g, is placed in the 100mL tri-that 40mL carrene band magnetic agitation is housedIn mouth flask, stir and make, after its dissolving, to get 0.30g sodium borohydride, under condition of ice bath, in one hour, divide and add reactant liquor three timesIn, the monitoring reaction of lamellae point sample carry out (thin-layer chromatography solvent, benzinum: acetone=4: 1), after raw material disappears completely,In reactant liquor, add saturated ammonium chloride solution 30mL, pour reactant liquor in separatory funnel layering, get organic phase, anhydrous sulphurEvaporated under reduced pressure solvent after acid sodium is dry, leaves standstill after adding 15mL acetic acid ethyl dissolution, and crystallization is N4-deoxidation quinocetone carbonylReduzate (Q4).
Claims (3)
1. the synthetic method of quinocetone metabolin N4-deoxidation quinocetone side chain carbonyl reduction product, is characterized in that following steps:
Taking mequindox as raw material, in suitable replacement amine azanol, methylamine, dimethylamine or triethylamine solution, reflux with selectivelyDeoxidation obtains N4-deoxidation mequindox, then carry out condensation with benzaldehyde, obtain N4-deoxidation quinocetone, further with sodium borohydrideIt is reduced, obtain N4-deoxidation quinocetone side chain carbonyl reduction product.
2. the synthetic method of quinocetone metabolin N4-deoxidation quinocetone side chain carbonyl reduction product according to claim 1,It is characterized in that, adopt replacement amine optionally to remove mequindox N as reducing agent4Position oxygen atom.
3. the synthetic method of quinocetone metabolin N4-deoxidation quinocetone side chain carbonyl reduction product according to claim 2,It is characterized in that, replace amine and adopt methylamine, dimethylamine or triethylamine, the rate of charge of substrate and reducing agent is 1:1～1:3.
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