CN103073512B - Synthetic method of quinoxaline-2-ethyl-3-methyl-N1-oxide - Google Patents
Synthetic method of quinoxaline-2-ethyl-3-methyl-N1-oxide Download PDFInfo
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- CN103073512B CN103073512B CN201310045003.2A CN201310045003A CN103073512B CN 103073512 B CN103073512 B CN 103073512B CN 201310045003 A CN201310045003 A CN 201310045003A CN 103073512 B CN103073512 B CN 103073512B
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- quinoxaline
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Abstract
The invention discloses a synthetic method of quinoxaline-2-ethyl-3-methyl-N1-oxide, which belongs to the technical field of biochemical industry. The molecular formula of the quinoxaline-2-ethyl-3-methyl-N1-oxide is C11H12N2O, and the quinoxaline-2-ethyl-3-methyl-N1-oxide is a quinoxaline drug metabolism product. The method comprises the following steps of: performing loop enclosing and reduction on benzofuraxan serving as a raw material to obtain a mixture of quinoxaline-2-ethyl-3-methyl-N1-oxide and N4-oxide; and performing column chromatography separation on the mixture to obtain a high-purity product. In the synthetic method, a simple and readily-available ordinary solvent is taken as a reaction medium, instruments and reaction conditions used in the method are very easy to implement, synthesis steps are simple, and an obtained product has higher purity.
Description
Technical field
The invention belongs to technical field of biochemical industry, be specifically related to a kind of synthetic method of quinoxaline-2-ethyl-3-methyl-N1-oxide compound.
Background technology
Quinoxaline medicine has quinoxaline-N
1, N
4one class chemosynthesis of-dioxide basic structure there is antibacterial and animal specific medicine that is growth promoting function, mainly comprise a class novel chiral synthon Quinocetone, mequindox etc. that China has independent intellectual property right.The safety issue of current ， quinoxaline medicine is the focus that food safety is paid close attention to, and the residual class of the veterinary drug in animal product can cause the harm of HUMAN HEALTH and produce direct obstacle to industry development.Therefore, the Scientific And Technical Problems that veterinary drug metabolism research department avoids residue of veterinary drug to solve, find when studying the pathways metabolism of this kind of medicine, this kind of medicine can react generation quinoxaline-2-ethyl-3-methyl-N1-oxide compound in animal body.There is no the synthesis patent of quinoxaline-2-ethyl-3-methyl-N1-oxide compound at present both at home and abroad, and bibliographical information is little, blank in order to make up this, and confirm its generation further, and study its toxic side effect, adopt chemical synthesis process to prepare quinoxaline-2-ethyl-3-methyl-N1-oxide compound to carry out contrast and seem very important, and the chemosynthesis of quinoxaline-2-ethyl-3-methyl-N1-oxide compound not only can provide standard substance for residual, the metabolism research of this type of medicine, also can provide reference method for same metabolite.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of quinoxaline-2-ethyl-3-methyl-N1-oxide compound.
Another object of the present invention is to provide the application as standard substance in the drug metabolism of research quinoxaline of above-mentioned quinoxaline-2-ethyl-3-methyl-N1-oxide compound.
Reaction equation involved is below:
a chemical synthesis process for quinoxaline-2-ethyl-3-methyl-N1-oxide compound, described oxide molecule formula is C
11h
12n
2o, its chemical structural formula as shown in (I),
（I）
Its feature exists, and comprises step as follows:
1) successively benzofuraxan, 2 pentanone, salt of wormwood and solvent are joined in reactor, instillation n-Butyl Amine 99, react at 20-60 DEG C after 1-6 hour and cool, obtain reaction mixture; Filtering salt of wormwood, underpressure distillation concentrates, and adds Virahol, puts in frozen water and separates out precipitation; Filter to obtain 2-Jia based quinoxaline-N1, N4-dioxide yellow solid; Wherein benzofuraxan, 2 pentanone and salt of wormwood mass ratio are 1:0.5:1.8-1:0.6:2, and n-Butyl Amine 99 and benzofuraxan mass ratio are 1-1.1:1;
2) by the product 2-Jia based quinoxaline-N1 of step 1), N4-dioxide dissolution with solvents, after adding reductive agent, standing and reacting is spent the night; Slowly add frozen water, sodium hydrate solid, add chloroform extraction twice, discard water layer, merge organic phase, with underpressure distillation after anhydrous sodium sulfate dehydration to about 2ml.Use pillar layer separation product, obtain compound shown in formula (I); Wherein 2-Jia based quinoxaline-N1, the mol ratio of N4-dioxide and reductive agent is 1:2-4.
After instilling n-Butyl Amine 99 described in step 1), the 5 hours reaction times at 40-60 DEG C.
Preferably, after instilling n-Butyl Amine 99 described in step 1), the 5 hours reaction times at 40 DEG C.
Solvent described in step 1) is one or more in methylene dichloride, trichloromethane, benzene, toluene.
Step 2) described in solvent be one or more in trichloromethane, methylene dichloride, benzene, toluene.
Step 2) described in reductive agent be phosphorus trichloride, trimethyl phosphite or sodium borohydride.
Quinoxaline medicine can react in animal body and generate above-mentioned quinoxaline-2-ethyl-3-methyl-N1-oxide compound, and above-mentioned quinoxaline-2-ethyl-3-methyl-N1-oxide compound can be used as the standard substance application in quinoxaline drug metabolism or residual research.
Beneficial effect of the present invention: the present invention successfully synthesizes quinoxaline-2-ethyl-3-methyl-N1-oxide compound, synthetic method adopts usual vehicle simple and easy to get as reaction medium, instrument and reaction conditions are also easy to realize, synthesis step is succinct, products obtained therefrom purity is very high, as standard substance, the domestic needs to its research can be met.
Accompanying drawing explanation
The hydrogen spectrogram of Fig. 1 Wei quinoxaline-2-ethyl-3-methyl-N1-oxide compound.
The carbon spectrogram of Fig. 2 Wei quinoxaline-2-ethyl-3-methyl-N1-oxide compound.
Embodiment
Below in conjunction with concrete case study on implementation, the present invention will be further explained, but concrete case study on implementation does not do any restriction to the present invention.
Embodiment 1
(1) quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide
Benzofuraxan (26.3g) is added, K2CO3(50g in 2 pentanone (17g)), CH2Cl2(200ml), in 1h, drip off n-Butyl Amine 99 (28.22g) at 30 DEG C under stirring, continue to stir 5h, filtering K2CO3, underpressure distillation concentrates, and adds Virahol, puts in frozen water and separates out precipitation.Filter, obtain the yellow solid of 4g containing a small amount of benzofuraxan, obtain yellow needle-like crystals 33.8g for several times through ethyl alcohol recrystallization.This temperature of reaction system, when more than 60 DEG C, can be blasted.
(2) quinoxaline-2-ethyl-3-methyl-N1-oxide compound
Take 1g quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide, add 30ml trichloromethane stirring and dissolving, add 5ml phosphorus trichloride room temperature reaction to spend the night, slowly add 100ml frozen water, 5g sodium hydrate solid, add twice trichloromethane 50ml to extract, discard water layer, merge organic phase, with 45 DEG C of underpressure distillation after 5g anhydrous sodium sulfate dehydration 1h to about 2ml.Upper prop (column chromatography condition: filler is silica gel G (200-300 order), eluent is ethyl acetate: sherwood oil (volume ratio 1:1) flow velocity is 1ml/min, every 10ml collects a cut, through TLC analysis, (condition is: stationary phase silica GF254, developping agent is ethyl acetate: sherwood oil (volume ratio 1:1), collect upper and lower 2 components respectively, all the other discard.The cut collecting at lower obtains 0.24g quinoxaline-2-ethyl-3-methyl-N1-oxide compound 45 DEG C of underpressure distillation to dry.Fusing point 77.8-78.7 DEG C.The hydrogen spectrogram of products therefrom and carbon spectrogram are as shown in Figure 1-2.
1H NMR（DMSO, 300MHz）δ 1.55 (m, 3H,CH
3), 2.86(s, 3H,CH
3), 5.79(m, 1H,CH
2), 5.90(m, 1H,CH
2), 7.80 (m, 2H, Ar-H), 8.01(m,1H, Ar-H),8.42(m,1H, Ar-H);
13C NMR(DMSO,75MHz) δ 19.271, 23.423, 39.702, 62.827, 128.963, 129.550, 131.166, 134.694,142.557, 144.630, 155.097。
Embodiment 2
(1) quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide
Benzofuraxan (26.3g) is added, K in 2 pentanone (17g)
2cO
3(50g), CHCl
3(200ml), under stirring, in 1h, drip off n-Butyl Amine 99 (28.22g) at 40 DEG C, continue to stir 5h, filtering K
2cO
3, underpressure distillation concentrates, and adds Virahol, puts in frozen water and separates out precipitation.Filter, obtain the yellow solid of 40g containing a small amount of benzofuraxan, obtain yellow needle-like crystals 30.7g for several times through ethyl alcohol recrystallization.This temperature of reaction system, when more than 60 DEG C, can be blasted.
(2) quinoxaline-2-ethyl-3-methyl-N1-oxide compound
Take 1g quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide, add 30ml trichloromethane stirring and dissolving, add 4.5g sodium borohydride room temperature reaction to spend the night, slowly add 100ml frozen water, 5g sodium hydrate solid, add twice trichloromethane 50ml to extract, discard water layer, merge organic phase, with 45 DEG C of underpressure distillation after 5g anhydrous sodium sulfate dehydration 1h to about 2ml.Upper prop (column chromatography condition: filler is silica gel G (200-300 order), eluent is ethyl acetate: sherwood oil (volume ratio 1:1) flow velocity is 1ml/min, every 10ml collects a cut, through TLC analysis, (condition is: stationary phase silica GF254, developping agent is ethyl acetate: sherwood oil (volume ratio 1:1), collect upper and lower 2 components respectively, all the other discard.The cut collecting at lower obtains 0.22g quinoxaline-2-ethyl-3-methyl-N1-oxide compound 45 DEG C of underpressure distillation to dry.
Embodiment 3
(1) quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide
Benzofuraxan (26.3g) is added, K in 2 pentanone (17g)
2cO
3(50g), CH
2cl
2(200ml), drip off n-Butyl Amine 99 (28.22g) under stirring at 50 DEG C in 1h, continue to stir 5h, filtering K2CO3, underpressure distillation concentrates, and adds Virahol, puts in frozen water and separates out precipitation.Filter, obtain the yellow solid of 40.8g containing a small amount of benzofuraxan, obtain yellow needle-like crystals 32.9g for several times through ethyl alcohol recrystallization.This temperature of reaction system, when more than 60 DEG C, can be blasted.
(2) quinoxaline-2-ethyl-3-methyl-N1-oxide compound
Take 1g quinoxaline-2-ethyl-3-methyl-N1, N4-dioxide, add 30ml methylene dichloride stirring and dissolving, add 5ml trimethyl phosphite room temperature reaction to spend the night, slowly add 100ml frozen water, 5g sodium hydrate solid, add twice methylene dichloride 50ml to extract, discard water layer, merge organic phase, with 45 DEG C of underpressure distillation after 5g anhydrous sodium sulfate dehydration 1h to about 2ml.Upper prop (column chromatography condition: filler is silica gel G (200-300 order), eluent is ethyl acetate: sherwood oil (volume ratio 1:1) flow velocity is 1ml/min, every 10ml collects a cut, through TLC analysis, (condition is: stationary phase silica GF254, developping agent is ethyl acetate: sherwood oil (volume ratio 1:1), collect upper and lower 2 components respectively, all the other discard.The cut collecting at lower obtains 0.21g quinoxaline-2-ethyl-3-methyl-N1-oxide compound 45 DEG C of underpressure distillation to dry.
Claims (4)
1. a chemical synthesis process for quinoxaline-2-ethyl-3-methyl-N1-oxide compound, described oxide molecule formula is C
11h
12n
2o, its chemical structural formula as shown in (I),
It is characterized in that, comprise step as follows:
1) successively benzo furoxan, 2 pentanone, salt of wormwood and solvent are joined in reactor, instillation n-Butyl Amine 99, react at 20-60 DEG C after 1-6 hour and cool, obtain reaction mixture; Filtering salt of wormwood, underpressure distillation concentrates, and adds Virahol, puts in frozen water and separates out precipitation; Filter to obtain 2-Jia based quinoxaline-N1, N4-dioxide yellow solid; Wherein benzofuraxan, 2 pentanone and salt of wormwood mass ratio are 1:0.5:1.8-1:0.6:2, and n-Butyl Amine 99 and benzofuraxan mass ratio are 1-1.1:1;
2) by step 1) product 2-Jia based quinoxaline-N1, N4-dioxide dissolution with solvents, after adding reductive agent, standing and reacting is spent the night; Slowly add frozen water, sodium hydrate solid, add chloroform extraction twice, discard water layer, merge organic phase, with underpressure distillation after anhydrous sodium sulfate dehydration to 2ml, use pillar layer separation product, obtain compound shown in formula (I); Wherein 2-Jia based quinoxaline-N1, the mol ratio of N4-dioxide and reductive agent is 1:2-4; Described solvent is one or more in trichloromethane, methylene dichloride, benzene, toluene; Described reductive agent is phosphorus trichloride or sodium borohydride.
2. synthetic method according to claim 1, is characterized in that, step 1) described in instill n-Butyl Amine 99 after, the 5 hours reaction times at 40-60 DEG C.
3. synthetic method according to claim 1, is characterized in that, step 1) described in instill n-Butyl Amine 99 after, the 5 hours reaction times at 40 DEG C.
4. synthetic method according to claim 1, is characterized in that, step 1) described in solvent be one or more in methylene dichloride, trichloromethane, benzene, toluene.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2719542A1 (en) * | 1976-05-03 | 1977-11-24 | Oreal | AGENT FOR TONING THE SKIN ON THE BASIS OF CHINOXALIN DERIVATIVES |
| CN102108065A (en) * | 2011-03-23 | 2011-06-29 | 浙江禾田化工有限公司 | Method for preparing 2-quinoxalinol |
-
2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2719542A1 (en) * | 1976-05-03 | 1977-11-24 | Oreal | AGENT FOR TONING THE SKIN ON THE BASIS OF CHINOXALIN DERIVATIVES |
| CN102108065A (en) * | 2011-03-23 | 2011-06-29 | 浙江禾田化工有限公司 | Method for preparing 2-quinoxalinol |
Non-Patent Citations (2)
| Title |
|---|
| Uber die Synthese von 2,3-Dialkylpyrazinen;Kurt Heyns等;《Chem. Ber.》;19811231;第114卷;第240-245页 * |
| 林树坤等.十一种2, 3 一二取代唆嘱琳-1,4-二氧化物抗菌荆的合成与谱学研究.《应用化学》.1988,第5卷(第4期),第17-23页. * |
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