CN103214425A - Preparation method of 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide - Google Patents
Preparation method of 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide Download PDFInfo
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Abstract
The invention discloses a preparation method of a 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide in the technical field of the biochemical engineering. A molecular formula of the 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide is C12H9N5O2 which is a quinoxaline drug metabolism product. The preparation method comprises the following steps of: with Benzofurazan as a raw material, carrying out ring-expanding, oxidizing, reducing, dehydrating and a condensing reaction to obtain the 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide. According to the preparation method of the 2-quinoxaline methylene hydrazine cyanoacetic acid-N4-oxide, a simple and easily available common solvent is used as a reaction medium, used apparatuses and reaction conditions are easy to realize, the synthesis steps are simple and the obtained product is higher in purity.
Description
Technical field
The invention belongs to technical field of biochemical industry, the preparation method of concrete a kind of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
Background technology
2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound (match of 1-deoxidation quinoline is many) belongs to the new variety quinoline of quinoxaline compounds and matches a kind of of many metabolites.Quinoxaline class medicine is the quinoxaline-N1 that has of a class chemosynthesis, N4-dioxide basic structure have antibiotic and animal specific medicine growth promoting function concurrently.Common quinoxaline class veterinary drug mainly comprises carbadox, olaquindox, and quinoline is matched many and Quinocetone etc.At present, the dependency of quinoxaline class veterinary drug and food safety has caused widely to be paid close attention to, and by to the residual research in the middle of animal product of quinoxaline class medicine, finds the absorption metabolic rule of medicine, thereby instructs rational use of drug, ensures food safety.Find that when the pathways metabolism of such medicine of research the quinoline match in this class medicine is many to generate 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound through metabolic reaction in vivo.In view of the patent of invention of up to the present not finding 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound, and mostly pertinent literature report direction is metaboilic level research and action effect research.For the background information that makes this class medicine is more perfect, and further prove the existence of this metabolite, the chemical preparation method of research 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound seems very important.The preparation of this metabolite also can auxiliary needle to the assay determination work of quinoxaline class drug toxicity toxicity aspect.
Patent " a kind of mequindox metabolic product and its production and application ", publication number CN 101648917A has also introduced a kind of synthetic method about the quinoxaline medicine metabolite.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound, 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound is as the metabolite of quinoxaline medicine, can be used as the standard substance in the various researchs of Dui quinoxaline medicine.
The chemical synthesis process of a kind of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound, described divided oxide minor is C
12H
9N
5O
2, its chemical structural formula is suc as formula shown in (I),
Comprise that step is as follows:
1) successively benzo furazan, acetone are joined in the reactor, both mass ratioes are 1:(1-2.5), after stirring treats that the benzo furazan dissolves fully, in 0.5-2 hour, splash into the acetone soln that is dissolved with hexahydropyridine to reactor, the mass ratio of benzo furazan and hexahydropyridine is (6-12): 1, and the volume ratio of hexahydropyridine and acetone is 1:10-20, the rising temperature of reaction system is to 50-60 ℃, continue to stir backflow 1-6 hour postcooling; Filter 3-methyl-quinoxalines-N1, N4-dioxide yellow solid;
2) with above-mentioned product 3-methyl-quinoxalines-N1, the N4-dioxide is dissolved in the solvent, carries out the oxidation back flow reaction under oxygenant; Temperature of reaction 50-110 ℃, reacted 1-6 hour, purifying obtains 2-formyl radical quinoxaline-N1, the N4-dioxide;
3) with above-mentioned product 2-formyl radical quinoxaline-N1, the N4-dioxide is dissolved in n-propyl alcohol, under reductive agent, reduce back flow reaction, reflux temperature 90-100 ℃, the reaction times is 0.5-1 hour, will be cooled to room temperature after the backflow, generation xanchromatic precipitation, use the methanol wash solid behind the suction filtration, obtain pure product 2-hydroxymethyl quinoxaline-N1, the N4-dioxide;
4) with above-mentioned product 2-hydroxymethyl quinoxaline-N1, N4-dioxide concentrated hydrochloric acid, dehydration generates 3-formyl radical quinoxaline-N1-oxide compound; 90-100 ℃ of dehydration reaction temperature, the dehydration reaction time is 0.5-1 hour; The available acetone recrystallization in reaction back is further purified 3-formyl radical quinoxaline-N1-oxide compound; 2-hydroxymethyl quinoxaline-N1 wherein, the mass ratio of N4-dioxide and concentrated hydrochloric acid is 1:(3-5);
5) in solvent, above-mentioned product 3-formyl radical quinoxaline-N1-oxide compound and neohydrazid are carried out condensation reaction, temperature of reaction is 10-30 ℃; Time is 1-3 hour; Cool off crystallization in 1-5 hour down at-1 to-4 ℃ then and obtain 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound; The mol ratio of reactant 3-formyl radical quinoxaline-N1-oxide compound and neohydrazid is 1:(1-1.5).
Solvent described in the step 1) is one or more in acetone, Virahol, methyl alcohol, the ethanol.
Temperature of reaction system described in the step 1) is 60 ℃.
Step 2) solvent described in is one or both in toluene, the ethyl acetate.
Step 2) oxygenant described in is a tin anhydride, itself and 3-methyl-quinoxalines-N1, and the mol ratio of N4-dioxide is (0.5-1.5): 1.
Step 2) purifying described in is: need be cooled to room temperature after the backflow, add gac and stir, filter, evaporated under reduced pressure obtains 2-formyl radical quinoxaline-N1, the N4-dioxide.
Reductive agent described in the step 3) is a trimethyl phosphite, itself and 2-formyl radical quinoxaline-N1, and the mol ratio of N4-dioxide is (1-1.5): 1.
Solvent described in the step 5) is one or both in water, the ethanol.
The reaction equation of above-mentioned reaction is:
Beneficial effect of the present invention: the present invention successfully synthesizes 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound, synthetic method adopt be simple and easy to usual vehicle as reaction medium, used instrument and reaction conditions also are easy to realize, synthesis step is succinct, products obtained therefrom purity is very high, can be used as standard substance, purity can reach more than 95%, satisfies domestic needs to its research.
Description of drawings:
Fig. 1 is the hydrogen spectrogram of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
Fig. 2 is the carbon spectrogram of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
Fig. 3 is the infrared figure of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
Fig. 4 is the high resolution mass spectrum figure of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
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.
The preparation of embodiment 1,2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
(1) 3-methyl-quinoxalines-N1, the N4-dioxide
In 80 ml acetone, add benzo furazan (27.2g), be under 50 ℃ the condition at system temperature, in 0.5 hour, drip off hexahydropyridine acetone soln (the 5ml hexahydropyridine is dissolved in the 50ml acetone) when stirring, under same temperature, continued stirring and refluxing 5 hours, have solid to generate, suction filtration is washed with acetone.Obtain the yellow solid about 20g.
(2) 2-formyl radical quinoxaline-N1, the N4-dioxide
Take by weighing 1,4 dioxy-2-Jia based quinoxaline 0.9g(5.1mmol) be dissolved in the 15ml ethyl acetate, add 0.75g(6.7mmol) in the tin anhydride reaction flask, back flow reaction 5 hours, temperature are 80 ℃.Be cooled to room temperature, add gac and stirred 0.5 hour, filter evaporated under reduced pressure.Get 0.39g sorrel solid 1,4-dioxy-2-formyl radical quinoxaline.
(3) 2-hydroxymethyl quinoxaline-N1, the N4-dioxide
1,4-dioxy-2-formyl radical quinoxaline (1.90 g 10mmol) are dissolved in the 30ml n-propyl alcohol, add 1. 24g(10mmol again) trimethyl phosphite, the reflux temperature is 100 ℃, 0.5 hour postcooling to 15 ℃ also produces yellow mercury oxide.Get 0.64g 1 with the methanol wash solid behind the suction filtration, 4-dioxy-2-hydroxymethyl quinoxaline.
(4) 3-formyl radical quinoxaline-N1-oxide compound
With 1,4-dioxy-2-hydroxymethyl quinoxaline (1.00 g, 5.20 mmol) adds 3ml (about 3.5g) concentrated hydrochloric acid, and solution is heated to 100 ℃ of stirrings 1 hour.The suction filtration reaction soln obtains small amount of solid, with the 0.57g 1-oxygen-3-formyl radical quinoxaline of acetone recrystallization.
(5) 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
Take by weighing 1.0g(5.74mmol) 1-oxygen-3-formyl radical quinoxaline, with 7ml 95% dissolve with ethanol.0.8g(8.08mmol) neohydrazid is dissolved in the 4ml water, adds reaction flask reaction 3 hours.Get 0.76g solid 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound.
The hydrogen spectrogram of the product 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound that obtains is as shown in Figure 1:
1H NMR(DMSO, 300MHz) δ: 4.43,7.83-7.89. 7.83-7.89,7.83-7.89,8.46,8.07,9.14,12.29; The carbon spectrogram is as shown in Figure 2:
13C NMR (DMSO, 75MHz) δ: 24.563,116.138,118.701,126.353,130.011,131.014,132.640,136.495,141.624,144.555,150.873,165.881; Its infrared figure is as shown in Figure 3: IR(KBr) ν: 3855.11,3736.68,3502.12,3434.27,3198.56,3084.25,2973.70,2261.02,1698.14,1579.20,1492.80,1392.24,1247.13,1152.57,773.85 cm
-1Its high resolution mass spectrum figure is as shown in Figure 4: HRMS(TOF) m/z(%): [M+H]
+256.0, the C of calculating
12H
10N
5O
2[M+H]
+256.244, actual [M+H] that finds
+256.3103.
The preparation of embodiment 2,2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
(1) 3-methyl-quinoxalines-N1, the N4-dioxide
In acetone (200ml, about 160g), add benzo furazan (68g), stir down and in 0.5 hour, drip off hexahydropyridine (the 7ml hexahydropyridine is dissolved in the 70ml acetone) at 50 ℃, continued stirring and refluxing 5 hours, temperature is 60 ℃, has solid to generate, and suction filtration is washed with acetone.Obtain the yellow solid about 47g.
(2) 2-formyl radical quinoxaline-N1, the N4-dioxide
Take by weighing 1,4 dioxy-2-Jia based quinoxaline 9g (about 51mmol) and be dissolved in the 150ml ethyl acetate, add in 7.5 g (about 67mmol) the tin anhydride reaction flask, temperature is that 80 ℃ of following reaction systems refluxed 5 hours.Be cooled to room temperature, add gac and stirred 0.5 hour, filter evaporated under reduced pressure.Get 4g sorrel solid 1,4-dioxy-2-formyl radical quinoxaline.
(3) 2-hydroxymethyl quinoxaline-N1, the N4-dioxide
1,4-dioxy-2-formyl radical quinoxaline (2 g, about 10.5mmol) is dissolved in the 35ml n-propyl alcohol, adds 1.5g (about 12.1mmol) trimethyl phosphite again, and temperature is 0.5 hour postcooling to 15 of 100 ℃ of following reflux ℃ and produces yellow mercury oxide.Get 1 g 1 with the methanol wash solid behind the suction filtration, 4-dioxy-2-hydroxymethyl quinoxaline.
(4) 3-formyl radical quinoxaline-N1-oxide compound
With 1,4-dioxy-2-hydroxymethyl quinoxaline (0.5 g) adds 2.1ml (about 1.18g) concentrated hydrochloric acid, and solution is heated to 100 ℃ of stirrings 1 hour.The suction filtration reaction soln obtains small amount of solid, with the 0.3 g 1-oxygen-3-formyl radical quinoxaline of acetone recrystallization.
(5) 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
Take by weighing 4.0g (about 23mmol) 1-oxygen-3-formyl radical quinoxaline, with 30 ml, 95% dissolve with ethanol.3.0 the about 30.3mmol of g() neohydrazid is dissolved in the 10 ml water, adds reaction flask reaction 3 hours.Get 3 g solid 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compounds.
The preparation of embodiment 3,2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
(1) 3-methyl-quinoxalines-N1, the N4-dioxide
Add benzo furazan (15 g) in acetone (19ml, about 15g), stir down and dripped off hexahydropyridine (2.5 ml are dissolved in the 25 ml acetone) at 60 ℃ in 0.5 hour, continued stirring and refluxing 5 hours at 60 ℃, have solid to generate, suction filtration is washed with acetone.Obtain the yellow solid about 10g.
(2) 2-formyl radical quinoxaline-N1, the N4-dioxide
Take by weighing 1,4 dioxy-about 28.4mmol of 2-first based quinoxaline 5 g() be dissolved in the 10 ml ethyl acetate, add in 4 g (about 35.7mmol) the tin anhydride reaction flask, 80 ℃ of following back flow reaction 5 hours.Be cooled to room temperature, add gac and stirred 0.5 hour, filter evaporated under reduced pressure.Get 1.8 g sorrel solids 1,4-dioxy-2-formyl radical quinoxaline.
(3) 2-hydroxymethyl quinoxaline-N1, the N4-dioxide
1,4-dioxy-2-formyl radical quinoxaline (10 g, about 52.6mmol) is dissolved in 300 ml n-propyl alcohols, adds the about 54mmol of 6.7g(again) trimethyl phosphite, at 0.5 hour postcooling to 15 of 100 ℃ of following reflux ℃ and produce yellow mercury oxide.Get 3 g 1 with the methanol wash solid behind the suction filtration, 4-dioxy-2-hydroxymethyl quinoxaline.
(4) 3-formyl radical quinoxaline-N1-oxide compound
With 1,4-dioxy-2-hydroxymethyl quinoxaline (2.5 g) adds 8 ml (about 9.4g) concentrated hydrochloric acid, and solution is heated to 100 ℃ of stirrings 1 hour.The suction filtration reaction soln obtains small amount of solid, with the 1.3 g 1-oxygen-3-formyl radical quinoxaline of acetone recrystallization.
(5) 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound
Take by weighing 5.0g (about 28.7mmol) 1-oxygen-3-formyl radical quinoxaline, with 40 ml, 95% dissolve with ethanol.3.5 the about 35.4mmol of g() neohydrazid is dissolved in the 10 ml water, adds reaction flask reaction 3 hours.Get 3.5 g solid 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compounds.
Claims (8)
1. the chemical synthesis process of 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound, described divided oxide minor is C
12H
9N
5O
2, its chemical structural formula is suc as formula shown in (I),
It is characterized in that, comprise that step is as follows:
1) successively benzo furazan, acetone are joined in the reactor, both mass ratioes are 1:(1-2.5), after stirring treats that the benzo furazan dissolves fully, in 0.5-2 hour, splash into the acetone soln that is dissolved with hexahydropyridine to reactor, the mass ratio of benzo furazan and hexahydropyridine is (6-12): 1, and the volume ratio of hexahydropyridine and acetone is 1:10-20, the rising temperature of reaction system is to 50-60 ℃, continue to stir backflow 1-6 hour postcooling; Filter 3-methyl-quinoxalines-N1, N4-dioxide yellow solid;
2) with above-mentioned product 3-methyl-quinoxalines-N1, the N4-dioxide is dissolved in the solvent, carries out the oxidation back flow reaction under oxygenant; Temperature of reaction 50-110 ℃, reacted 1-6 hour, purifying obtains 2-formyl radical quinoxaline-N1, the N4-dioxide;
3) with above-mentioned product 2-formyl radical quinoxaline-N1, the N4-dioxide is dissolved in n-propyl alcohol, under reductive agent, reduce back flow reaction, reflux temperature 90-100 ℃, the reaction times is 0.5-1 hour, will be cooled to room temperature after the backflow, generation xanchromatic precipitation, use the methanol wash solid behind the suction filtration, obtain pure product 2-hydroxymethyl quinoxaline-N1, the N4-dioxide;
4) with above-mentioned product 2-hydroxymethyl quinoxaline-N1, N4-dioxide concentrated hydrochloric acid, dehydration generates 3-formyl radical quinoxaline-N1-oxide compound; 90-100 ℃ of dehydration reaction temperature, the dehydration reaction time is 0.5-1 hour; The available acetone recrystallization in reaction back is further purified 3-formyl radical quinoxaline-N1-oxide compound; 2-hydroxymethyl quinoxaline-N1 wherein, the mass ratio of N4-dioxide and concentrated hydrochloric acid is 1:(3-5);
5) in solvent, above-mentioned product 3-formyl radical quinoxaline-N1-oxide compound and neohydrazid are carried out condensation reaction, temperature of reaction is 10-30 ℃; Time is 1-3 hour; Cool off crystallization in 1-5 hour down at-1 to-4 ℃ then and obtain 2-quinoxaline methylene diazanyl cyanoacetic acid-N4-oxide compound; The mol ratio of reactant 3-formyl radical quinoxaline-N1-oxide compound and neohydrazid is 1:(1-1.5).
2. synthetic method according to claim 1 is characterized in that, solvent described in the step 1) is one or more in acetone, Virahol, methyl alcohol, the ethanol.
3. synthetic method according to claim 1 is characterized in that, temperature of reaction system described in the step 1) is 60 ℃.
4. synthetic method according to claim 1 is characterized in that step 2) described in solvent be in toluene, the ethyl acetate one or both.
5. synthetic method according to claim 1 is characterized in that step 2) described in oxygenant be tin anhydride, itself and 3-methyl-quinoxalines-N1, the mol ratio of N4-dioxide is (0.5-1.5): 1.
6. synthetic method according to claim 1 is characterized in that step 2) described in purifying be: need be cooled to room temperature after the backflow, add gac and stir, filter, evaporated under reduced pressure obtains 2-formyl radical quinoxaline-N1, the N4-dioxide.
7. synthetic method according to claim 1 is characterized in that, reductive agent described in the step 3) is a trimethyl phosphite, itself and 2-formyl radical quinoxaline-N1, and the mol ratio of N4-dioxide is (1-1.5): 1.
8. synthetic method according to claim 1 is characterized in that, solvent described in the step 5) is one or both in water, the ethanol.
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| CN110218195A (en) * | 2018-03-02 | 2019-09-10 | 上海安谱实验科技股份有限公司 | A kind of quinoxaline -2- the carboxylic acid and its synthetic method of stable isotope labeling |
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Cited By (2)
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| CN110218195A (en) * | 2018-03-02 | 2019-09-10 | 上海安谱实验科技股份有限公司 | A kind of quinoxaline -2- the carboxylic acid and its synthetic method of stable isotope labeling |
| CN110218195B (en) * | 2018-03-02 | 2022-08-09 | 上海安谱实验科技股份有限公司 | Stable isotope labeled quinoxaline-2-carboxylic acid and synthesis method thereof |
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