CN101016267A - Chemical synthesis method for 3-methylquinoxaline-2-carboxylic acid - Google Patents
Chemical synthesis method for 3-methylquinoxaline-2-carboxylic acid Download PDFInfo
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- CN101016267A CN101016267A CN 200710051391 CN200710051391A CN101016267A CN 101016267 A CN101016267 A CN 101016267A CN 200710051391 CN200710051391 CN 200710051391 CN 200710051391 A CN200710051391 A CN 200710051391A CN 101016267 A CN101016267 A CN 101016267A
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- carboxylic acid
- methyl
- quinoxaline
- olaquindox
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Abstract
The invention discloses a synthesizing method of 3-methyl quinoxaline-2-carboxyl acid, which comprises the following steps: adopting 2-[(N-2-hydroxyethyl) amino formyl]-3-methyl quinoxaline-1, 4-dioxide (quinoxalcohol) as raw material; reducing through potassium iodide or sodium hydrosulfite; hydrolyzing product through alkaline; adjusting pH value through acid; obtaining the product with high receiving rate and low cost.
Description
Technical field
The invention belongs to the chemical preparation technical field, be specifically related to the chemical synthesis process of a kind of 3-methyl-quinoxaline-2-carboxylic acid.
Background technology
3-methyl-quinoxaline-2-carboxylic acid is one of olaquindox metabolite, because it leaves animal body at last, is defined as the residual marker of olaquindox at present and (sees OLaquindox (WHO Food Additives Series 27,33).Olaquindox belongs to quinoxaline-1, and 4-dioxide class medicine is artificial synthetic broad spectrum antibiotic, and the Ceng Zuowei growth promoter is applied in poultry, fowl, the aquaculture.The synthetic method that present standard substance about the residual marker of detection olaquindox in the animal food are 3-methyl quinoline woods-2-carboxylic acid is not seen relevant patent documentation and non-patent literature report as yet.
Summary of the invention
The object of the invention is to provide the chemical synthesis process of a kind of 3-of being applicable to methyl-quinoxaline-2-carboxylic acid, to satisfy the preparation of this compound.
The present invention reaches by following scheme:
The synthetic method of a kind of 3-methyl-quinoxaline-2-carboxylic acid, its step is as follows:
(1) olaquindox and reductive agent potassiumiodide or V-Brite B are pressed amount of substance than 1: 1～1: 10 (as preferred version, the amount of substance of described reductive agent potassiumiodide or V-Brite B is 4～10 times of olaquindox) add in the reaction flask and add water to dissolving, 70～90 ℃ are stirred and react 1～5h, reaction finishes with trichloromethane or the mixed liquid of ethyl acetate extraction reaction, dewater with anhydrous magnesium sulfate, rotary evaporation gets the intermediate product olaquindox and takes off the dioxy thing; As preferred reaction conditions, the mole number of described reductive agent is 4～10 times of raw material olaquindox; Temperature of reaction is 70～90 ℃; Reaction solvent is a water; Reaction times is that 1～5h obtains the intermediate product olaquindox and takes off the dioxy thing.
(2) step (1) gained intermediate product olaquindox is taken off the dioxy thing and be dissolved in 1～5molL
-1Be prepared into mixed solution in the sodium hydroxide solution, be heated to the 3～9h that refluxes, regulate pH of mixed to 3～5 (preferred version is that pH is transferred to 3) with acid solution, filtering reaction mixes liquid, wash three times, be dried to constant weight, get 3-methyl-quinoxaline-2-crude carboxylic acid, through recrystallizing methanol, get target product 3-methyl-quinoxaline-2-carboxylic acid again.
The present invention has the following advantages:
1. raw material is easy to get: raw material used in the present invention and reagent olaquindox, sodium hydroxide, methyl alcohol, trichloromethane, concentrated hydrochloric acid, anhydrous magnesium sulfate etc. all are raw material commonly used and reagent, obtain easily.
2. conversion unit, reaction conditions are realized easily: the present invention only adopts instruments such as thermostat water bath, filter flask, prolong, and the equipment used cost is low; Working method is simple.
3. environmental pollution is little: agents useful for same relative toxicity of the present invention is less, and experiment material is polluted little.
Description of drawings
Fig. 1 is the UV scanning collection of illustrative plates (is solvent with methyl alcohol) of synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid;
Fig. 2 is the infrared scan collection of illustrative plates (KBr) of synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid;
Fig. 3 is synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid
13CNMR spectrogram (CDCL
3);
Fig. 4 is synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid
1HNMR spectrogram (CDCL
3);
Fig. 5 is synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid mass spectrum.
Embodiment
(1) in the 500mL reaction flask, add olaquindox 0.1moL, water 250mL, 70 ℃ are stirred and add 0.4moL V-Brite B powder down, behind 70 ℃ of following stirring reaction 1h, stop heating, be cooled to room temperature, with the mixed liquid of 600mL chloroform extraction reaction, merge, use anhydrous magnesium sulfate drying.Through the Rotary Evaporators evaporate to dryness, obtain faint yellow residual solids 14.5g again, yield is 63%, uses recrystallizing methanol, gets flaxen pressed powder, and promptly the intermediate product olaquindox takes off the dioxy thing.
(2) adding olaquindox in reaction flask takes off dioxy thing 9.28g and becomes mixed solution, backflow 3h, stopped reaction with 1moL/L sodium hydroxide solution 250mL, transfer described pH of mixed to 3 with concentrated hydrochloric acid, treat that the incarnadine material separates out fully, filter, wash three times, leach thing and dry to constant weight, obtain incarnadine solid 3-methyl-quinoxaline-2-crude carboxylic acid 5.37g, productive rate is 71%, after recrystallizing methanol, obtain the sorrel needle-like crystal, be target product 3-methyl-quinoxaline-pure product of 2-carboxylic acid, 152 ℃ of fusing points.
Embodiment 2
(1) in the 500mL reaction flask, adds olaquindox 0.1moL, water 250mL, be warming up to 80, add the 0.6moL V-Brite B behind reaction 3h under 80 ℃, stop heating, be cooled to room temperature, with the mixed liquid of 600mL chloroform extraction reaction, merge, with the moisture in the anhydrous magnesium sulfate drying organic phase.Filter organic phase, with organic phase Rotary Evaporators evaporate to dryness, obtain faint yellow residual solids 13.8g, yield is 60%, uses recrystallizing methanol, gets flaxen powder, and promptly the intermediate product olaquindox takes off the dioxy thing.
(2) the intermediate product olaquindox that adds step (1) preparation in reaction flask takes off dioxy thing 9.24g and becomes mixed solution with 5moL/L sodium hydroxide 250mL, behind the backflow 6h, stopped reaction, transfer mixed solution to pH4 with concentrated hydrochloric acid, leave standstill, treat that the incarnadine material separates out fully, filter, wash three times, leach thing and in baking oven, dry to constant weight, obtain incarnadine solid 3-methyl-quinoxaline-2-crude carboxylic acid 5.18g, productive rate is 69%, after recrystallizing methanol, obtains the sorrel needle-like crystal, be target product 3-methyl-quinoxaline-pure product of 2-carboxylic acid, fusing point: 151 ℃.
Add olaquindox 0.1moL in the 500mL reaction flask, water 250mL is warming up to 90 ℃, adds 1moL V-Brite B powder, adds in the 30min; Behind 90 ℃ of following stirring reaction 5h, be cooled to room temperature, divide the mixed liquid of extractive reaction three times with the 600mL trichloromethane, merge, with the moisture in the anhydrous magnesium sulfate drying organic phase, with organic phase evaporated under reduced pressure on Rotary Evaporators, obtain faint yellow residual solids 14.3g, yield is 62%, uses recrystallizing methanol, get flaxen powder, be the intermediate product olaquindox and take off the dioxy thing.All the other preparation processes are with embodiment 1.Obtain the sorrel needle-like crystal, be target product 3-methyl-quinoxaline-pure product of 2-carboxylic acid, fusing point: 151 ℃.
Embodiment 4
The reaction conditions that provides according to embodiment 1 potassiumiodide of amount of substance such as is changed to the reductive agent V-Brite B, and reaction is finished smoothly, faint yellow residual solids 13.2g, yield is 57%.
In reaction flask, add olaquindox and take off dioxy thing 9.25g and become mixed solution, behind the backflow 9h with 5moL/L sodium hydroxide 250mL.Stopped reaction, transfer mixed solution to pH5 with concentrated hydrochloric acid, leave standstill and treat that the incarnadine material separates out fully, filter, wash three times, leach thing in baking oven 50 ℃ ℃ dry to constant weight, obtain incarnadine solid 3-methyl-quinoxaline-2-crude carboxylic acid 5.35g, productive rate is 71%, after recrystallizing methanol, obtain the sorrel needle-like crystal, be 3-methyl-quinoxaline-pure product of 2-carboxylic acid, fusing point: 153 ℃.
The product that the present invention prepares through ultraviolet, infrared, nucleus magnetic resonance, mass spectrum, and the ultimate analysis detected result as follows:
The UV scanning collection of illustrative plates of 3-methyl-quinoxaline-2-carboxylic acid (AgiLent 8453 ultraviolet spectrophotometers), methyl alcohol is solvent, promptly there are the two or more unsaturated link(age)s of conjugated in the absorption peak about λ=241nm for heteroaromatic ring compounds k band absorbs; Low strong absorption band about λ=321nm has the existence of carbonyl or conjugation carbonyl in the description architecture; See Fig. 2.
The infrared scan collection of illustrative plates of 3-methyl-quinoxaline-2-carboxylic acid (ExcaLibur Series infrared spectrometer), the KBr compressing tablet, as can be seen from the figure the corresponding relation of each main absorption peak and each group is: 3448cm
-1, 2449cm
-1, υ
OHThe stretching vibration of carboxylic hydroxyl; 3078cm
-1, 3038cm
-1, υ
C-HPhenyl ring=CH stretching vibration; 1718cm
-1, υ
C=OCarbonylic stretching vibration; 1562cm
-1, 1487cm
-1Phenyl ring C=C stretching vibration; 1387cm
-1, the vibration of methyl symmetric curvature; 906cm
-1, the outer formation vibration of OH face; 748cm
-1, the outer formation vibration of phenyl ring CH face; See Fig. 3.
3-methyl-quinoxaline-2-carboxylic acid
1HNMR spectrogram (Mercury 400 nuclear magnetic resonance analyser), deuterium is a solvent for trichloromethane.0.00PPm be the internal standard substance tetramethylsilane
1The chemical shift of H; 7.26ppm be the solvent deuterium for trichloromethane
1The chemical shift of H; 3.180ppm be-CH
3H-shift; 7.826～8.155ppm is the H-shift of quinoxaline group; 8.6～12.0PPm broad peak is the chemical shift of-COOH association hydrogen bond; See Fig. 4.
3-methyl-quinoxaline-2-carboxylic acid
13CNMR spectrogram (Mercury 400 nuclear magnetic resonance analyser), deuterium is a solvent for trichloromethane.24.302PPm be-CH
3 13The C displacement; 128.803～155.095ppm is the quinoxaline group
13The C displacement, 163.364PPm is-COOH
13The C displacement; See Fig. 5.
3-methyl-quinoxaline-2-carboxylic acid mass spectrum (Finnigan TRACE MS mass spectrograph), source temperature 200, electron energy 70eV, quality of scanning scope 35-300u.M/z 188 is the molecular ion peak of 3-methyl-quinoxaline-2-carboxylic acid among the figure; M/z144 is that molion is sloughed CO
2The fragment ion peak of molecule; M/z 170 is that molecule is sloughed H
2The fragment ion peak of O molecule, this fragment ion peak is then sloughed the fragment that CO obtains m/z 142.6, and this fragment peak is a base peak; M/z 76 may be the fragment peak of phenyl ring; The ion of m/z 102 may be the rearrangement formation by complexity; See Fig. 6.
Synthetic results of elemental analyses of the present invention is as shown in table 1.Table 1 is synthetic 3-methyl-quinoxaline of the present invention-2-carboxylic acid ultimate analysis data (adopting Vario EL III elemental analyser to analyze), and the calculated value of N, C, H is respectively: N, 14.89%; C, 63.83%; H, 4.26%.The measured value one of N, C, H is respectively: N, 14.71%; C, 63.64%; H, 4.19%.The measured value two of N, C, H is respectively: N, 14.64%; C, 63.92%; H, 4.213%.This compound results of elemental analyses show N, C, three kinds of elements of H measured value and calculated value differ all in 3 ‰.
The ultimate analysis of table 13-methyl quinoline woods-2-carboxylic acid
| 3-methyl quinoline woods-2-carboxylic acid | N element (%) | C element (%) | H element (%) |
| Measured |
14.710 | 63.640 | 4.190 |
| Measured value 2 | 14.640 | 63.920 | 4.213 |
| Theoretical value | 14.89 | 63.83 | 4.26 |
Claims (3)
1, the synthetic method of a kind of 3-methyl-quinoxaline-2-carboxylic acid, its step is as follows:
1) olaquindox and reductive agent potassiumiodide or V-Brite B were added water to dissolving than 1: 4～1: 10 in the adding reaction flask by amount of substance, 70～90 ℃ are stirred and react 1～5h, reaction finishes with trichloromethane or the mixed liquid of ethyl acetate extraction reaction, dewater with anhydrous magnesium sulfate, rotary evaporation gets the intermediate product olaquindox and takes off the dioxy thing;
2) step 1) gained intermediate product olaquindox takes off the dioxy thing and is dissolved in 1～5molL
-1Become mixed solution in the sodium hydroxide solution, be heated to the 3～9h that refluxes, regulate described pH of mixed to 3～5 with acid solution, the described mixed liquid of filtering reaction is washed three times, is dried to constant weight, get 3-methyl-quinoxaline-2-crude carboxylic acid,, get target product 3-methyl-quinoxaline-2-carboxylic acid again through recrystallizing methanol.
2, the synthetic method of the described 3-methyl-quinoxaline of claim 1-2-carboxylic acid, wherein the amount of substance of potassiumiodide in the step 1) or V-Brite B is 4～10 times of olaquindox.
3, the synthetic method of the described 3-methyl-quinoxaline of claim 1-2-carboxylic acid, wherein step 2) used acid is concentrated hydrochloric acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104693131A (en) * | 2013-12-06 | 2015-06-10 | 平原县伟峰永驻科技有限公司 | Efficient chemical synthesizing method of 3-methyl-quinoxaline-2-carboxylic acid |
| CN105061338A (en) * | 2014-11-20 | 2015-11-18 | 平原县伟峰永驻科技有限公司 | 3-methyl-quinoxaline-2-carboxylic acid chemical synthesis method based on ionic liquid system |
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| CH538488A (en) * | 1969-12-12 | 1973-06-30 | Hoffmann La Roche | Process for the preparation of heterocyclic compounds |
| CN1041796C (en) * | 1993-03-02 | 1999-01-27 | 周逸锦 | Long-acting kangliling antidysenteric suspended injection for animals and preparation method thereof |
| AUPR527801A0 (en) * | 2001-05-25 | 2001-06-21 | University Of Sydney, The | Animal husbandry iii |
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| CN104693131A (en) * | 2013-12-06 | 2015-06-10 | 平原县伟峰永驻科技有限公司 | Efficient chemical synthesizing method of 3-methyl-quinoxaline-2-carboxylic acid |
| CN105061338A (en) * | 2014-11-20 | 2015-11-18 | 平原县伟峰永驻科技有限公司 | 3-methyl-quinoxaline-2-carboxylic acid chemical synthesis method based on ionic liquid system |
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