CN110218195B - Stable isotope labeled quinoxaline-2-carboxylic acid and synthesis method thereof - Google Patents
Stable isotope labeled quinoxaline-2-carboxylic acid and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a stable isotope labeled quinoxaline-2-carboxylic acid and a synthesis preparation method thereof, which comprises the following steps: s1: carrying out condensation reaction on methylglyoxal-1-oxime under acid catalysis and aniline labeled by a stable isotope, and then adding phosphorus oxychloride to react to obtain 2-methyl quinoxaline labeled by the stable isotope; s2: oxidizing the stable isotope labeled 2-methyl quinoxaline obtained in the step S1 by selenium dioxide and hydrogen peroxide, and performing post-treatment purification to obtain stable isotope labeled quinoxaline-2-carboxylic acid. According to the synthesis method of the stable isotope labeled quinoxaline-2-carboxylic acid, the prepared quinoxaline-2-carboxylic acid has good quality, the purity is more than 98%, and the isotope abundance is more than 99%; the raw materials are easy to obtain and cheap, the synthesis cost is low, the steps are few, and the operation is simple and rapid; the obtained target compound can be used as an internal standard substance for detecting the residue of the olaquindox and carbalkoxy veterinary drugs, so that the detection cost is greatly reduced.
Description
Technical Field
The invention relates to a synthetic method of an organic compound, in particular to quinoxaline-2-carboxylic acid labeled by a stable isotope and a synthetic method thereof.
Background
Carbalkoxy is a spectrum antibacterial drug developed by the U.S. pyroxene company, has good antibacterial performance, protein assimilation and obvious effects of promoting the growth of livestock and improving the feed conversion rate. Therefore, carbadox becomes an excellent variety of the quinoxaline growth promoter, and has been widely used in the breeding industry in seventy years of the last century. However, researchers find that carbalkoxy is easy to accumulate in animals, and after the carbalkoxy is metabolized, metabolic products have obvious toxic and side effects of carcinogenesis, teratogenesis and the like. Based on this, countries such as europe and the united states have banned the drug. China also announces that carbadox belongs to forbidden veterinary drugs through Ministry of agriculture 560, and quinoxaline-2-carboxylic acid is used as a residual marker of carbadox, and a series of detection methods of Ministry of China and Ministry of agriculture are provided.
At present, the detection method aiming at the carbalkoxy residue mainly comprises a high performance liquid chromatography and a liquid chromatography tandem mass spectrometry. GB/T20746-2006 and GB/T22984-2008 are detection methods for carbalkoxy and residues thereof in beef, pork and milk by national standards, and liquid chromatography tandem mass spectrometry is adopted. In both methods, stable isotope-labeled quinoxaline-2-carboxylic acid is required as an internal standard. The internal standard substance completely depends on import at present, is expensive, no company provides a product which is independently researched and developed at home, and no relevant literature and patent report about a synthetic method of the internal standard substance at home and abroad. Therefore, the development of a synthetic method of the stable isotope labeled quinoxaline-2-carboxylic acid has very remarkable social and economic benefits.
Disclosure of Invention
The invention aims to solve the technical problem of providing stable isotope labeled quinoxaline-2-carboxylic acid and a synthesis method thereof, wherein the preparation raw materials are cheap and easy to obtain, and the target compound with purity and isotope abundance of more than 98 percent can be obtained by only two simple synthesis steps, so that the use requirement of the target compound as an internal standard substance during detection is met.
The technical scheme adopted by the invention for solving the technical problems is to provide a synthesis method of quinoxaline-2-carboxylic acid labeled by stable isotope, which comprises the following steps: s1: carrying out condensation reaction on methylglyoxal-1-oxime under the catalysis of organic acid and aniline labeled by a stable isotope, adding phosphorus oxychloride, and reacting to obtain 2-methyl quinoxaline labeled by the stable isotope; s2: oxidizing the stable isotope labeled 2-methyl quinoxaline obtained in the step S1 by selenium dioxide to obtain stable isotope labeled 2-formaldehyde quinoxaline, and further oxidizing the stable isotope labeled 2-formaldehyde quinoxaline by hydrogen peroxide to obtain stable isotope labeled quinoxaline-2-carboxylic acid; and performing post-treatment purification, namely adjusting the pH of the solution subjected to suction filtration and solid removal to be alkaline by using an alkaline solution, washing by using an organic solvent, adjusting the pH of the solution to be acidic, and separating out a target compound from the solution to obtain the quinoxaline-2-carboxylic acid labeled by the stable isotope.
Further, the organic acid in step S1 is formic acid, acetic acid, propionic acid or trifluoroacetic acid, and the reaction solvent is benzene, toluene or nitrobenzene.
Further, in the step S1, the molar ratio of methylglyoxal-1-oxime to stable isotope-labeled aniline is 1.2-1.0: 1, and the molar ratio of phosphorus oxychloride to stable isotope-labeled aniline is 2.0-3.0: 1.
Further, the reaction temperature in the step S1 is 90-100 ℃, and the reaction time is 4-6 hours.
Further, the reaction solvent in step S2 is one of 1, 4-dioxane, ethyl acetate, and tetrahydrofuran.
Further, in the step S2, the molar ratio of selenium dioxide to the stable isotope-labeled 2-methyl quinoxaline is 1.5 to 2.0:1, and the molar ratio of hydrogen peroxide to the stable isotope-labeled 2-methyl quinoxaline is 1.2 to 1.0: 1.
Further, the oxidation reaction temperature of the selenium dioxide in the step S2 is 80-100 ℃, and the reaction time is 3-5 hours; the temperature of the oxydol oxidation reaction is 20-60 ℃, and the reaction time is 2-12 hours.
Another technical solution of the present invention to solve the above technical problems is to provide a stable isotope labeled quinoxaline-2-carboxylic acid having a molecular structure as shown below, which is prepared by the above synthesis method
Compared with the prior art, the invention has the following beneficial effects: the stable isotope labeled quinoxaline-2-carboxylic acid and the synthesis method thereof provided by the invention take cheap and easily available stable isotope labeled aniline and methylglyoxal-1-oxime as raw materials, and can obtain the stable isotope labeled quinoxaline-2-carboxylic acid through two steps of synthesis steps with simple operation, so that the preparation cost is low, the operation steps are few and simple, the purity and the isotope abundance of the stable isotope labeled quinoxaline-2-carboxylic acid are over 98 percent, and the stable isotope labeled quinoxaline-2-carboxylic acid can be completely used as an internal standard substance for detecting the residue of olaquindox and carbalkoxy veterinary drugs.
Description of the figures
Fig. 1 is a liquid phase tandem mass spectrum of a stable isotope labeled quinoxaline-2-carboxylic acid in an example of the present invention.
FIG. 2 is a high performance liquid chromatogram of quinoxaline-2-carboxylic acid labeled with a stable isotope in an example of the present invention
FIG. 3 is a 1H NMR spectrum of quinoxaline-2-carboxylic acid labeled with a stable isotope in an example of the present invention
Detailed Description
The invention is further described below with reference to the figures and examples.
The invention provides a synthesis method of stable isotope labeled quinoxaline-2-carboxylic acid, which comprises the following steps:
s1: reacting methylglyoxal-1-oxime under the catalysis of organic acid with aniline labeled by stable isotope, adding phosphorus oxychloride, and reacting to obtain 2-methyl quinoxaline labeled by stable isotope.
The organic acid is formic acid, acetic acid, propionic acid or trifluoroacetic acid, and the reaction solvent is benzene, toluene or nitrobenzene; the molar ratio of the pyruvaldehyde-1-oxime to the stable isotope labeled aniline is 1.2-1.0: 1, and the molar ratio of the phosphorus oxychloride to the stable isotope labeled aniline is 2.0-3.0: 1; the reaction temperature is 90-100 ℃, and the reaction time is 4-6 hours.
S2: oxidizing the stable isotope labeled 2-methyl quinoxaline obtained in the step S1 by selenium dioxide to obtain stable isotope labeled 2-formaldehyde quinoxaline, and further oxidizing the stable isotope labeled 2-formaldehyde quinoxaline by hydrogen peroxide to obtain stable isotope labeled quinoxaline-2-carboxylic acid; and performing post-treatment purification, namely adjusting the pH of the solution subjected to suction filtration and solid removal to be alkaline by using an alkaline solution, washing by using an organic solvent, adjusting the pH of the solution to be acidic, and separating out a target compound from the solution to obtain the quinoxaline-2-carboxylic acid labeled by the stable isotope.
The oxidation reaction solvent is one of 1, 4-dioxane, ethyl acetate and tetrahydrofuran; the molar ratio of the selenium dioxide to the stable isotope labeled 2-methyl quinoxaline is 1.5-2.0: 1, and the molar ratio of the hydrogen peroxide to the stable isotope labeled 2-methyl quinoxaline is 1.2-1.0: 1; the oxidation reaction temperature of the selenium dioxide is 80-100 ℃, and the reaction time is 3-5 hours; the temperature of the oxydol oxidation reaction is 20-60 ℃, and the reaction time is 2-12 hours.
The synthetic route of the invention is as follows:
the invention takes methylglyoxal-1-oxime and stable isotope labeled aniline as raw materials, and can prepare the target compound with purity more than 98% and isotope abundance more than 99% through two-step simple organic reaction. Fig. 1 is a liquid phase mass spectrum of the stable isotope-labeled quinoxaline-2-carboxylic acid, the abscissa of (a) of fig. 1 and the abscissa of (b) of fig. 1 respectively represent a peak appearance time and a mass-to-charge ratio, and it can be seen from the graph that a peak of 179.1 appears in the peak mass spectrum of the stable isotope-labeled quinoxaline-2-carboxylic acid, which is consistent with a theoretical calculation value of 179.1, and a mass after a hydrogen ion is bound to a target compound, and fragment ion peaks of 164.1, 133.2 and 106.2 appear at the same time, the spectrum of which is consistent with a standard spectrum of the target compound, and the isotope abundance is 99.6% as determined by a liquid phase mass spectrometry. Fig. 2 is a high performance liquid chromatogram of a stable isotope-labeled quinoxaline-2-carboxylic acid, and the purity was determined to be 98.8% by an area normalization method. Fig. 3 is a 1H NMR spectrum of stable isotope labeled quinoxaline-2-carboxylic acid, solution is deuterated dimethyl sulfoxide, and abscissa is chemical shift. From the 1H NMR spectrum, a peak of hydrogen on the nitrogen heterocycle appeared at 9.45, but no peak appeared in the hydrogen on the benzene ring, indicating that the hydrogen atom on the benzene ring was a deuterium atom and was not dropped off during the reaction.
Example 1
S1: 50mL of benzene was placed in a reaction flask, and 2.45g of stable isotope-labeled aniline and 2.3g of pyruvaldehyde-1-oxime were dissolved in 50mL of benzene, and 0.5mL of acetic acid was added and the mixture was allowed to react at 90 ℃ for 1 hour. After completion, the reaction flask was cooled to room temperature, and 30mL of acetonitrile was added to the reaction flask and dissolved therein. 5.7mL of phosphorus oxychloride was dispersed in 30mL of acetonitrile, and the mixture was dropped into the reaction flask through a constant pressure dropping funnel for 10 to 15 minutes. After the dropping, the reaction flask was left at 90 ℃ for 4 hours.
After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into 100mL of a cold saturated sodium bicarbonate solution. Extracted three times with 50mL portions of ethyl acetate. After the organic phases were combined, they were washed once with 100mL of a saturated sodium bicarbonate solution and once with 100mL of a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After drying, the solvent was removed by suction filtration. Separating and purifying by column chromatography. Eluting the product with an eluant of a 4:1 molar ratio of n-hexane to ethyl acetate. Finally, 2.73g of the stable isotope labeled 2-methyl quinoxaline is obtained, and the yield is 74 percent.
S2: 1.48g of the isotope-labeled 2-methylquinoxaline obtained above was dissolved in 50mL of 1, 4-dioxane, and then 1.65g of selenium dioxide was added thereto, and the mixture was left at 100 ℃ for reaction for 3 hours. After the reaction is finished, cooling to room temperature, adding 1.1mL of hydrogen peroxide, and reacting at 25 ℃ for 12 hours.
After the reaction, the solid was removed by suction filtration, and after removing part of the solvent by rotary evaporation, 50mL of a 5% NaOH solution was added, followed by washing with 50mL of dichloromethane a total of three times. Finally, the pH of the solution is adjusted to 2-3 by concentrated hydrochloric acid in the water phase, a large amount of red precipitate is found to be separated out, and after suction filtration, the precipitate is vacuumized and dried to obtain 1.45g of a target product with the yield of 81.5%.
Example 2
S1: 60mL of toluene was placed in a reaction flask, 1.96g of stable isotope-labeled aniline and 2.08g of pyruvaldehyde-1-oxime were dissolved in 60mL of toluene, 0.6mL of formic acid was added, and the mixture was left to react at 100 ℃ for 2 hours. After completion, the reaction mixture was cooled to room temperature, and 40mL of acetonitrile was added to the reaction flask and dissolved therein. 4.5mL of phosphorus oxychloride is dispersed in 30mL of acetonitrile, and the mixture is dripped into the reaction bottle by using a constant pressure dropping funnel and dripped out within 10-15 minutes. After the dropping, the reaction flask was placed at 100 ℃ for 2 hours. The post-treatment was the same as in step S1 in example 1, to give 1.99g of stable isotope-labeled 2-methylquinoxaline with a yield of 69%.
S2: 1.99g of the stable isotope-labeled 2-methylquinoxaline obtained above was dissolved in 80mL of ethyl acetate, followed by addition of 2.98g of selenium dioxide and reaction at 80 ℃ for 5 hours. After the reaction is finished, the reaction solution is cooled to room temperature, 1.7mL of hydrogen peroxide is added, and the reaction solution is placed at 50 ℃ for reaction for 4 hours. The post-treatment was the same as in step S2 in example 1, to obtain 2.05g of the objective product in 85% yield.
Example 3
S1: 20mL of nitrobenzene was placed in a reaction flask, 0.49g of stable isotope-labeled aniline and 0.48g of pyruvaldehyde-1-oxime were dissolved in 20mL of nitrobenzene, and 0.2mL of trifluoroacetic acid was added and the mixture was allowed to react at 90 ℃ for 1.5 hours. After completion, the reaction flask was cooled to room temperature, and 20mL of acetonitrile was added to the reaction flask and dissolved therein. 1.2mL of phosphorus oxychloride was dispersed in 10mL of acetonitrile, and the mixture was dropped into the reaction flask through a constant pressure dropping funnel for 10 to 15 minutes. After the dropping, the reaction flask was placed at 100 ℃ for reaction for 3 hours. The post-treatment was the same as in step S1 in example 1, to give 0.58g of stable isotope-labeled 2-methylquinoxaline with a yield of 79%.
S2: 0.44g of the stable isotope-labeled 2-methylquinoxaline obtained above was dissolved in 15mL of tetrahydrofuran, followed by addition of 0.60g of selenium dioxide and reaction at 90 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, adding 0.35mL of hydrogen peroxide, and reacting at 60 ℃ for 2 hours. The post-treatment was the same as in step S2 in example 1, to obtain 0.48g of the objective product in a yield of 90%.
In conclusion, the synthesis method of the stable isotope labeled quinoxaline-2-carboxylic acid provided by the invention has the advantages that the prepared quinoxaline-2-carboxylic acid has good quality, the purity is more than 98%, and the isotope abundance is more than 99%; the raw materials are easy to obtain and cheap, the synthesis cost is low, the steps are few, and the operation is simple and rapid; the obtained target compound can be used as an internal standard substance for detecting the residues of the olaquindox and carbalkoxy veterinary drugs, so that the detection cost is greatly reduced.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. A synthetic method of stable isotope labeled quinoxaline-2-carboxylic acid comprises the following steps:
s1: carrying out condensation reaction on methylglyoxal-1-oxime under the catalysis of organic acid and aniline labeled by a stable isotope, adding phosphorus oxychloride, and reacting to obtain 2-methyl quinoxaline labeled by the stable isotope;
s2: oxidizing the stable isotope labeled 2-methyl quinoxaline obtained in the step S1 by selenium dioxide to obtain stable isotope labeled 2-formaldehyde quinoxaline, and further oxidizing the stable isotope labeled 2-formaldehyde quinoxaline by hydrogen peroxide to obtain stable isotope labeled quinoxaline-2-carboxylic acid; performing post-treatment purification, namely adjusting the pH of the solution subjected to suction filtration and solid removal to be alkaline by using an alkaline solution, washing by using an organic solvent, adjusting the pH of the solution to be acidic, and separating out a target compound from the solution to obtain the quinoxaline-2-carboxylic acid labeled by the stable isotope;
the stable isotope labeled aniline has a molecular structure as shown in the following:
the stable isotope labeled 2-methyl quinoxaline has a molecular structure shown as follows:
the stable isotope labeled 2-formaldehyde quinoxaline has a molecular structure as shown in the following:
the stable isotope labeled quinoxaline-2-carboxylic acid has a molecular structure shown as follows:
2. the method of claim 1, wherein the organic acid in step S1 is formic acid, acetic acid, propionic acid or trifluoroacetic acid, and the reaction solvent is benzene, toluene or nitrobenzene.
3. The synthesis method of claim 1, wherein in step S1, the molar ratio of methylglyoxal-1-oxime to stable isotope-labeled aniline is 1.2 to 1.0:1, and the molar ratio of phosphorus oxychloride to stable isotope-labeled aniline is 2.0 to 3.0: 1.
4. The synthesis method according to claim 1, wherein the reaction temperature in step S1 is 90-100 ℃ and the reaction time is 4-6 hours.
5. The method of claim 1, wherein the reaction solvent in step S2 is one of 1, 4-dioxane, ethyl acetate and tetrahydrofuran.
6. The synthesis method according to claim 1, wherein in step S2, the molar ratio of selenium dioxide to the stable isotope-labeled 2-methyl quinoxaline is 1.5 to 2.0:1, and the molar ratio of hydrogen peroxide to the stable isotope-labeled 2-methyl quinoxaline is 1.2 to 1.0: 1.
7. The synthesis method of claim 1, wherein the selenium dioxide in step S2 is oxidized at 80-100 ℃ for 3-5 hours; the temperature of the oxydol oxidation reaction is 20-60 ℃, and the reaction time is 2-12 hours.
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