CN100427474C - Method of preparing 3-methylquinoxaline-2-carboxylic acid - Google Patents
Method of preparing 3-methylquinoxaline-2-carboxylic acid Download PDFInfo
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- CN100427474C CN100427474C CNB2007100513924A CN200710051392A CN100427474C CN 100427474 C CN100427474 C CN 100427474C CN B2007100513924 A CNB2007100513924 A CN B2007100513924A CN 200710051392 A CN200710051392 A CN 200710051392A CN 100427474 C CN100427474 C CN 100427474C
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Abstract
The invention discloses a synthesizing method of 3-methyl quinoxaline-2-carboxyl acid, which comprises the following steps: adopting benzo furan as raw material; reacting with acetoacetidin to produce middle produce 3-methyl-2-quinoxaline methanoic acid carbethoxy-1, 4-dioxygen catalyzed by calcium hydroxide; reducing 3-methyl-2-quinoxaline methanoic acid carbethoxy-1, 4-dioxygen and sodium hydrosulfite to produce 3-methyl-2-quinoxaline ethyl formate; hydrolyzing 3-methyl-2-quinoxaline ethyl formate and sodium hydroxide; adjusting pH value through condensed sulfuric acid; extracting; recrystallizing; obtaining the product.
Description
Technical field
The present invention relates to the chemical preparation technical field, be specifically related to the preparation method 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 preparation method that present standard substance about the residual marker of detection olaquindox in the animal food are 3-methyl quinoline woods-2-carboxylic acid does not see relevant patent documentation and non-patent literature report as yet.
Summary of the invention
The object of the invention is to provide the preparation method of a kind of 3-of being applicable to methyl-quinoxaline-2-carboxylic acid.
It is achieved through the following technical solutions:
The synthetic method of a kind of 3-methyl-quinoxaline-2-carboxylic acid, its step is as follows:
1) in reaction flask, adds calcium hydroxide, benzo furazan, Virahol successively, be heated to 60 ℃, dropwise add methyl aceto acetate, wherein methyl aceto acetate is 1: 1～5: 1 with the benzo furazan by the amount of substance ratio, Virahol is 3～5 times of benzo furazan amount of substance, back flow reaction 5h, be cooled to room temperature after,-20 ℃ are spent the night, suction filtration, filter cake water, methyl alcohol wash successively, and filter cake is dried to constant weight, get intermediate product 3-methyl-2-quinoxaline ethyl formate-1, the 4-dioxy;
2) adding the intermediate product of step 1) gained in reaction flask, is solvent with the second alcohol and water, is cooled to 10 ℃, add V-Brite B, wherein V-Brite B is 5～10 times of benzo furazan amount of substance, reflux, cooling, extract three times, merge organic phase, behind the anhydrous magnesium sulfate drying, filter, precipitation, resistates gets intermediate product 3-methyl-2-quinoxaline ethyl formate with ether and normal hexane recrystallization;
3) adding step 2 in reaction flask) the intermediate product 3-methyl-2-quinoxaline ethyl formate of gained, sodium hydroxide solution is heated to the 5～10h that refluxes, cooling, regulate pH to 5～7 with acid solution, use chloroform extraction, anhydrous sodium sulfate drying, recrystallizing methanol, separate out yellow solid, filter, after the solid constant weight, promptly obtain target product 3-methyl-quinoxaline-2-carboxylic acid.
According to the basic thought of foregoing invention, optimization step of the present invention is:
The step 1) methyl aceto acetate is pressed amount of substance with the benzo furazan and was added than 3: 1.
The calcium hydroxide of step 1) is adding in 1: 2.5 with the benzo furazan by the amount of substance ratio.
Step 2) the reflux time is 7～9h.
Step 2) ether and normal hexane are mixing in 1: 2 by volume.
Step 2) V-Brite B is 6～9 times of benzo furazan amount of substance.
The described concentration of sodium hydroxide solution of step 3) is 1～5molL
-1
The used acid of step 3) is that concentration is 1～4molL
-1Sulfuric acid.
The present invention has the following advantages:
1, raw material is easy to get: raw material used in the present invention and reagent benzo furazan, Virahol, methyl aceto acetate, sodium hydroxide, dehydrated alcohol, trichloromethane, anhydrous magnesium sulfate etc. all are raw material commonly used and reagent, obtain easily.
2, conversion unit, operational condition etc. realize 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.
Description of drawings
Fig. 1 is the UV scanning collection of illustrative plates (methyl alcohol is solvent) 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 reaction flask of 500mL, adds calcium hydroxide 0.04mol successively
,Benzo furazan 0.1mol, Virahol 3.27mol are heated to 60 ℃.After dropwise adding methyl aceto acetate 0.1mol, back flow reaction 5h, be cooled to room temperature after, in-20 ℃ of freeze overnight, suction filtration, filter cake 100mL water, 50mL washed with methanol, filter cake dries to constant weight, and obtains intermediate product 3-methyl-2-quinoxaline ethyl formate-1, the 4-dioxy.
(2) add above-mentioned gained intermediate product 3-methyl-2-quinoxaline ethyl formate-1 in reaction flask, 4-dioxy 0.1mol uses dehydrated alcohol 270mL, water 30mL stirs 0.5h, after treating to dissolve fully, be cooled to about 10 ℃, add V-Brite B 0.6mol in batches, temperature rising reflux 4h.To room temperature, add 200mL cold water, stir 30min.With the solution chloroform extraction, merge organic phase, use anhydrous magnesium sulfate drying.Filter precipitation.Resistates is 1: 2 mixed solvent recrystallization with ether and normal hexane by volume, faint yellow needle-like crystal 4.32g, i.e. intermediate product 3-methyl-2-quinoxaline ethyl formate, melting range is 72-74 ℃.
(3) in reaction flask, add intermediate product 3-methyl～2-quinoxaline ethyl formate 4.3g and 1molL that step (2) prepares
-1Sodium hydroxide solution 100mL stirs, and behind the back flow reaction 5h, cooling in ice-water bath, is used 1molL
-1Sulphur acid for adjusting pH value to 5 leaves standstill 0.5h.Solution is transferred to the 1000mL separating funnel, divides 3 extractions, merge organic phase with the 600mL trichloromethane, use anhydrous magnesium sulfate drying, the rotary evaporation desolventizing gets yellow solid, uses recrystallizing methanol, solution was placed 3 days in-20 ℃ of refrigerators, separate out yellow solid, decompress filter, oven dry, promptly get target product 3-methyl-quinoxaline-2-carboxylic acid, fusing point is 152 ℃.
(1) answer in the bottle at 500mL, add calcium hydroxide 0.04mol successively, benzo furazan 0.1mol, Virahol 3.27mol is heated to 80 ℃.Dropwise add methyl aceto acetate 0.5mol, after dropwising, back flow reaction 10h.Stop heating, be cooled to room temperature ,-20 ℃ of freeze overnight.Suction filtration, filter cake 100mL water, 50mL washed with methanol, filter cake is dried to constant weight, and obtaining the faint yellow solid powder is intermediate product 3-methyl-2-quinoxaline ethyl formate-1, and 4-dioxy, fusing point are about 140 ℃.
(2) in reaction flask, add intermediate product 3-methyl-2-quinoxaline ethyl formate-1 that step (1) prepares, 4-dioxy 12.4g, ethanol 120mL, water 180mL, stir 0.5h, fully after the dissolving, with being cooled to about 10 ℃, add V-Brite B 0.9mol in batches, heat up backflow 10h.After being cooled to room temperature, add 100mL cold water, stir 30min.Divide three extractions with solution with trichloromethane 600mL, merge organic phase, anhydrous magnesium sulfate drying.Filter precipitation.Resistates is that 1: 2 mixed solvent carries out recrystallization with ether and normal hexane volume ratio, faint yellow needle-like crystal, i.e. intermediate product 3-methyl-2-quinoxaline ethyl formate, melting range: 72 ℃～74 ℃.
(3) in reaction flask, add intermediate product 3-methyl-2-quinoxaline ethyl formate 5.4g that step (2) prepares, 5molL
-1Sodium hydroxide 125mL, vigorous stirring, back flow reaction, behind the reaction 5h, cooling.In ice-water bath, use 4molL
-1Sulphur acid for adjusting pH value to 7 leaves standstill 0.5h.Solution is transferred to the 1000mL separating funnel, divide 3 extractions with the 600mL trichloromethane, merge organic phase, use anhydrous magnesium sulfate drying, rotary evaporation is removed the trichloromethane solvent, get yellow solid, use recrystallizing methanol, separate out yellow solid, decompress filter, the gained solid is dried to constant weight by the method for embodiment 1, promptly gets target product 3-methyl-quinoxaline-2-carboxylic acid, fusing point: 152 ℃ (decomposition).
The target product 3-methyl-quinoxaline-2-carboxylic acid of the present invention preparation is as follows through multiple instrument such as ultraviolet, infrared, nucleus magnetic resonance, mass spectrum and ultimate analysis and analysis means detected result:
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.Referring to Fig. 1.
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.Referring to Fig. 2.
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. 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; 7.260ppm 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.Referring to Fig. 4.
3-methyl-quinoxaline-2-carboxylic acid mass spectrum (FinniganTRACE MS mass spectrograph), 200 ℃ of source temperature, electron energy 70eV, quality of scanning scope 35-300u.M/z 188 is the molecular ion peak of 3-methyl-quinoxaline among the figure; M/z 144 sloughs CO for molion
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.Referring to Fig. 5.
The results of elemental analyses of synthetic 3-methyl quinoline woods of the present invention-2-carboxylic acid (adopting Vario EL III elemental analyser to analyze) as shown in table 1, 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%.The 3-methyl quinoline woods of the present invention preparation-2-carboxylic acid 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 the target product 3-methyl quinoline woods-2-carboxylic acid of table 1 the present invention preparation
| 3-methyl quinoline woods-2-carboxylic acid | N element (%) | C element (%) | H element (%) |
| Measured |
14.710 | 63.640 | 4.190 |
| Measured |
14.640 | 63.920 | 4.213 |
| Theoretical value | 14.89 | 63.83 | 4.26 |
Claims (8)
1, the preparation method of a kind of 3-methyl-quinoxaline-2-carboxylic acid, its step is as follows:
1) in reaction flask, adds calcium hydroxide, benzo furazan, Virahol successively, be heated to 60 ℃, dropwise add methyl aceto acetate, wherein methyl aceto acetate is 1: 1～5: 1 with the benzo furazan by the amount of substance ratio, Virahol is 3～5 times of benzo furazan amount of substance, back flow reaction 5h, be cooled to room temperature after,-20 ℃ are spent the night, suction filtration, filter cake water, methyl alcohol wash successively, and filter cake is dried to constant weight, get intermediate product 3-methyl-2-quinoxaline ethyl formate-1, the 4-dioxy;
2) adding the intermediate product of step 1) gained in reaction flask, is solvent with the second alcohol and water, is cooled to 10 ℃, add V-Brite B, wherein V-Brite B is 5～10 times of benzo furazan amount of substance, reflux, cooling, extract three times, merge organic phase, behind the anhydrous magnesium sulfate drying, filter, precipitation, resistates gets intermediate product 3-methyl-2-quinoxaline ethyl formate with ether and normal hexane recrystallization;
3) adding step 2 in reaction flask) the intermediate product 3-methyl-2-quinoxaline ethyl formate of gained, sodium hydroxide solution is heated to the 5～10h that refluxes, cooling, regulate pH to 5～7 with acid solution, use chloroform extraction, anhydrous sodium sulfate drying, recrystallizing methanol, separate out yellow solid, suction filtration after the solid constant weight, promptly obtains target product 3-methyl-quinoxaline-2-carboxylic acid.
2, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein the step 1) methyl aceto acetate is pressed amount of substance than adding in 3: 1 with the benzo furazan.
3, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein the calcium hydroxide of step 1) is 1: 2.5 with the benzo furazan by the amount of substance ratio.
4, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein step 2) the reflux time be 7～9h.
5, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein step 2) ether and normal hexane be to mix at 1: 2 by volume.
6, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein step 2) V-Brite B is 6～9 times of benzo furazan amount of substance.
7, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein the described concentration of sodium hydroxide solution of step 3) is 1～5molL
-1
8, the preparation method of 3-methyl-quinoxaline according to claim 1-2-carboxylic acid, wherein the used acid of step 3) is that concentration is 1～4molL
-1Sulfuric acid.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3759912A (en) * | 1969-12-12 | 1973-09-18 | Hoffmann La Roche | Quinoxalines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3759912A (en) * | 1969-12-12 | 1973-09-18 | Hoffmann La Roche | Quinoxalines |
Non-Patent Citations (4)
| Title |
|---|
| An Improved and Efficient Synthesis ofQuinoxalinecarboxamide I ,4- Dioxides from Benzof uroxanand Acetoacetamides in the Presence of Calcium Salts3). (2. STUMMH, .-J. NICLAS*.J. Prakt. Chem.,,Vol.331 No.5. 1989 |
| An Improved and Efficient Synthesis ofQuinoxalinecarboxamide I ,4- Dioxides from Benzof uroxanand Acetoacetamides in the Presence of Calcium Salts3). (2. STUMMH, .J. NICLAS*.J. Prakt. Chem.,Vol.331 No.5. 1989 * |
| 喹喔啉双氮氧化物衍生物的合成及其体外乏氧选择性细胞毒作用. 吴艳芬等.中国药物化学杂志，第7卷第3期. 1997 |
| 喹喔啉双氮氧化物衍生物的合成及其体外乏氧选择性细胞毒作用. 吴艳芬等.中国药物化学杂志，第7卷第3期. 1997 * |
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