CN104710371A - Preparation method of trifluoromethyl-containing benzo pyrazinamide - Google Patents
Preparation method of trifluoromethyl-containing benzo pyrazinamide Download PDFInfo
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- CN104710371A CN104710371A CN201310687096.9A CN201310687096A CN104710371A CN 104710371 A CN104710371 A CN 104710371A CN 201310687096 A CN201310687096 A CN 201310687096A CN 104710371 A CN104710371 A CN 104710371A
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- trifluoromethyl
- benzo
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- pyrazinamide
- acid amide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Abstract
The present invention discloses trifluoromethyl-substituted benzo pyrazinamide and a preparation method thereof. Pyrazinamide has good germicidal effect on resistant bacteria, and can be widely used in clinical application. Pyrazinamide is widely used in anti tuberculosis drugs, and trifluoromethyl group has important value in medicines. The synthesis of the pyrazinamide by introduction of the trifluoromethyl group has important significance and potential medicine value. The trifluoromethyl-substituted benzo pyrazinamide is synthesized by three step reaction, first, 4-trifluoromethyl-1, 2-o-phenylenediamine can be synthesized from 4-boric acid-1, 2-o-phenylendiamine and trifluoromethyl trimethyl silicone in the presence of cuprous iodide as a catalyst, second, trifluoromethyl-substituted benzo pyrazine is synthesized from the 4-trifluoromethyl-1, 2-o-phenylenediamine and oxalaldehyde in alkaline conditions by use of ethanol and water as a solvent, and third, the final product trifluoromethyl-substituted benzo pyrazinamide can be synthesized from the trifluoromethyl-substituted benzo pyrazine and methanamide in strong acid conditions under the ferrous sulfate catalytic effect.
Description
Technical field
The present invention relates to a kind of is the novel method that trifluoromethyl replacement benzamide prepared by raw material by 4-boric acid-1,2-O-Phenylene Diamine, belongs to chemical material and pharmaceutical field.
Background technology
Pyrazinoic acid amide has excellent anti-microbial activity, is synthesized first in 1936 by people such as Dalmer.Discovered in recent years pyrazinoic acid amide has good germicidal action to persisting bacilli, therefore in wide clinical application, it and Rifampin have become the most effective antibacterials in SCC.Due to trifluoromethyl (CF
3) there is the characteristic such as electron-withdrawing, lipotropy and stable C-F key by force, be introduced into significantly can change compound in organic compound acidity, dipole moment, polarity, lipotropy and its chemistry and metabolic stability.The compound of trifluoromethyl is used widely in fields such as medicine, agricultural chemicals and materials.Due to the widespread use of pyrazinoic acid amide in antitubercular agent, and the important value of trifluoromethyl group in medicine.Pyrazinoic acid amide introduces trifluoromethyl, and synthesis trifluoromethyl replaces the significant and very large potential medical value of benzo pyrazinoic acid amide.The report of relevant aromatics introducing trifluoromethyl was as follows in the past: Hartwig, J.F.; Etal.Angew.Chem.Int.Ed.2011,50,3793; Khan, B.A.; Et al.Chem.Eur.J.2012,18,1577; MacMillan, W.C.; Et al.Nature.2011,480,225.
Summary of the invention
The object of this invention is to provide a kind of preparation method of new trifluoromethyl benzo pyrazinoic acid amide.
According to technical scheme provided by the invention, the feature that described a kind of 4-boric acid-1,2-O-Phenylene Diamine synthesis trifluoromethyl replaces benzo pyrazinoic acid amide novel method comprises following three step synthesis steps:
The first step: 4-Trifluoromethyl-1,2-O-Phenylene Diamine synthetic schemes
4-boric acid-1,2-O-Phenylene Diamine and trifluoromethyl trimethylsilane are joined in reaction vessel by the amount of certain mol proportion, adds CuI as catalyzer, add certain equivalent 1,10-phenanthroline again, benzoyl peroxide, cesium fluoride, is solvent with DMF, reacts 12h at ambient temperature; The ratio of the amount of substance of described 4-boric acid-1,2-O-Phenylene Diamine, trifluoromethyl trimethyl silicane, catalyzer, 1,10-phenanthroline, benzoyl peroxide, cesium carbonate is 1:1.3:1:1.1:2:1.2.Filter, through 200 ~ 300 object silica column purification, after 20 ~ 50ml sherwood oil in advance drip washing silicagel column, adopt leacheate to carry out wash-out, leacheate flow velocity is 1 ~ 2ml/min, and elution time is 3 ~ 6h, after desolventizing, namely obtain described 4-Trifluoromethyl-1,2-O-Phenylene Diamine.
The reaction equation of described method is:
Described alkali is cesium fluoride; Described organic solvent is DMF; Ethyl acetate and the sherwood oil mixing solutions of described leacheate to be mass ratio be 1:10
The consumption of described alkali is 1.2 times of 4-boric acid-1,2-O-Phenylene Diamine.
Described temperature of reaction is normal temperature.
The described reaction times is 12h.
Second step: the synthetic schemes of trifluoromethyl benzo pyrazine
By 4-Trifluoromethyl-1,2-O-Phenylene Diamine and oxalic dialdehyde are put in reactor with certain mol ratio, take potassium tert.-butoxide as alkali, ethanol: water=2:1 is reaction system solvent, react 12 hours under reflux state, described 4-Trifluoromethyl-1,2-O-Phenylene Diamine, oxalic dialdehyde the ratio of amount of substance be 1:1.2.Filter, through 200 ~ 300 object silica column purification, after the pre-drip washing silicagel column of 20 ~ 50ml sherwood oil, adopt leacheate to carry out wash-out, leacheate flow velocity is 1 ~ 2ml/min, and elution time is 6h, after desolventizing, namely obtains described trifluoromethyl benzo pyrazine.
The reaction equation of described method is:
Described alkali is potassium tert.-butoxide; Described solvent is the mixture of the second alcohol and water of 2:1; Ethyl acetate and the sherwood oil mixing solutions of described leacheate to be mass ratio be 1:10.
The consumption of described potassium tert.-butoxide is 4-Trifluoromethyl-1,1.5 times of 2-O-Phenylene Diamine.
Described temperature of reaction is reflux at 100 DEG C.
The described reaction times is 12h.
3rd step: trifluoromethyl replaces benzo pyrazinoic acid amide synthetic schemes
Trifluoromethyl benzo pyrazine is added drop-wise in the vitriol oil of stirring and forms trifluoromethyl benzo pyrazine vitriol by this reaction, join in 0 DEG C of methane amide after crystal being pulverized after cooling crystallize out in batches, add tertbutyl peroxide and ferrous sulfate reaction 30min simultaneously.Pyrazinoic acid amide is obtained with chloroform extraction after the excessive formic acid of underpressure distillation.Through 200 ~ 300 object silica column purification, after 20 ~ 50ml sherwood oil in advance drip washing silicagel column, adopt leacheate to carry out wash-out, leacheate flow velocity is 1 ~ 2ml/min, and elution time is 4h, after desolventizing, namely obtains described trifluoromethyl benzo pyrazinoic acid amide.
The reaction equation of described method is:
Described solvent is N-Methyl pyrrolidone; Described leacheate is mass ratio is the ethyl acetate of 1:10 and the mixing solutions of sherwood oil.
The consumption of described ferrous sulfate is 1 times of trifluoromethyl benzo pyrazine.
Described temperature of reaction is 0 DEG C.
The described reaction times is 0.5h.
Embodiment
Embodiment 1:
Magnetic stir bar is being housed, in the 100ml there-necked flask of T-valve, add 4-boric acid-1, the 2-O-Phenylene Diamine of 1.52g, the trifluoromethyl trimethyl silicane of 1.846g, 0.18g cuprous iodide, the benzoyl peroxide of 2.42g, 1 of 1.08g, the cesium fluoride of 10-phenanthroline, 0.91g, the DMF of 25ml makees solvent, stirs, and biexhaust pipe vacuumizes, displacement nitrogen, in triplicate, react under room temperature, TLC plate following response.
By obtained reaction soln suction filtration, filtrate vacuumizes at oil pump, pressure reducing and steaming solvent under 0MPa, the solid obtained is dissolved in methylene dichloride, and through 200 ~ 300 object silica column purification, gained solid is 4-Trifluoromethyl-1,2-O-Phenylene Diamine, obtains white solid 0.297g, and productive rate is 17%.
Embodiment 2:
Magnetic stir bar is being housed, in the 100ml there-necked flask of T-valve, add 4-boric acid-1, the 2-O-Phenylene Diamine of 1.52g, the trifluoromethyl trimethyl silicane of 1.846g, the cuprous iodide of 1.81g, the benzoyl peroxide of 4.84g, 1 of 2.178g, the cesium fluoride of 10-phenanthroline, 1.824g, the DMF of 25ml makees solvent, stirs, and biexhaust pipe vacuumizes, displacement nitrogen, in triplicate, react under room temperature, TLC plate following response.
By obtained reaction soln suction filtration; Filtrate vacuumizes at oil pump, pressure reducing and steaming solvent under 0MPa, and the solid obtained is dissolved in methylene dichloride, and through 200 ~ 300 object silica column purification, gained solid is 4-Trifluoromethyl-1, and 2-O-Phenylene Diamine obtains white solid 1.443g, and productive rate is 82%.
Embodiment 3:
In the 100ml there-necked flask that magnetic stir bar, prolong, thermometer are housed, add the 4-Trifluoromethyl-1 of 1.76g, the oxalic dialdehyde of 2-O-Phenylene Diamine, 0.696g, the potassium tert.-butoxide of 1.68g, the ethanol of 20ml and the water of 10ml make mixed solvent, in air, normal-temperature reaction, TLC plate following response.
By obtained reaction soln suction filtration, filtrate vacuumizes under Rotary Evaporators, pressure reducing and steaming solvent under 0MPa, the solid obtained is dissolved in methylene dichloride, through 200 ~ 300 object silica column purification, gained solid is trifluoromethyl and replaces benzopyrazines, and obtain faint yellow solid 0.852g, productive rate is 43%.
Embodiment 4:
In the 100ml there-necked flask that magnetic stir bar, prolong, thermometer are housed, add the 4-Trifluoromethyl-1 of 1.76g, the oxalic dialdehyde of 2-O-Phenylene Diamine, 0.696g, the potassium tert.-butoxide of 1.68g, the ethanol of 20ml and the water of 10ml make mixed solvent, in air, stir, oil bath is heated to backflow, TLC plate following response.
By obtained reaction soln suction filtration, filtrate vacuumizes under Rotary Evaporators, pressure reducing and steaming solvent under 0MPa, the solid obtained is dissolved in methylene dichloride, through 200 ~ 300 object silica column purification, gained solid is trifluoromethyl and replaces benzopyrazines, and obtain faint yellow solid 1.82g, productive rate is 92%.
Embodiment 5:
Be equipped with in magnetic stir bar there-necked flask, 1.98g trifluoromethyl benzo pyrazine is added drop-wise in the 5ml vitriol oil of stirring and forms trifluoromethyl benzo pyrazine vitriol, join in the methane amide under normal temperature after crystal being pulverized after cooling crystallize out in batches, add 20ml tertbutyl peroxide and 20ml N-Methyl pyrrolidone, TLC plate following response simultaneously.React through time two days later, the display of TLC plate still has large content of starting materials to exist.
Embodiment 6:
Be equipped with in magnetic stir bar there-necked flask, 1.98g trifluoromethyl benzo pyrazine is added drop-wise in the 5ml vitriol oil of stirring and forms trifluoromethyl benzo pyrazine vitriol, join after crystal being pulverized after cooling crystallize out in methane amide under normal temperature and 20ml N-Methyl pyrrolidone in batches, add 20ml tertbutyl peroxide and 1.39g ferrous sulfate, TLC plate following response simultaneously.React after 4 hours, after the excessive formic acid of underpressure distillation, obtain pyrazinoic acid amide with chloroform extraction.Through 200 ~ 300 object silica column purification, gained solid is trifluoromethyl and replaces benzo pyrazinoic acid amide, and obtain white solid 0.385g, productive rate is 16%.
Embodiment 7:
Be equipped with in magnetic stir bar there-necked flask, 1.98g trifluoromethyl benzo pyrazine is added drop-wise in the 10ml vitriol oil of stirring and forms trifluoromethyl benzo pyrazine vitriol, join after crystal being pulverized after cooling crystallize out in methane amide at 0 DEG C and 20ml N-Methyl pyrrolidone in batches, add 20ml tertbutyl peroxide and 2.78g ferrous sulfate, TLC plate following response simultaneously.After reaction 0.5h, after the excessive formic acid of underpressure distillation, obtain pyrazinoic acid amide with chloroform extraction.Through 200 ~ 300 object silica column purification, gained solid is trifluoromethyl and replaces benzo pyrazinoic acid amide, and obtain white solid 0.745g, productive rate is 31%.
Claims (4)
1. trifluoromethyl replaces a preparation for benzo pyrazinoic acid amide, and its molecular formula is C
10h
6n
3oF
3, structural formula is
2. trifluoromethyl according to claim 1 replaces benzo pyrazinoic acid amide syntheti c route step one, it is characterized in that the concrete steps of described reaction are as follows: by 4-boric acid-1,2-O-Phenylene Diamine and trifluoromethyl trimethylsilane are put in reactor according to the mol ratio of 1:1.3, cuprous iodide is catalyzer, add appropriate N, dinethylformamide (DMF), reacts under normal temperature, TLC plate following response.After reaction 12h, suction filtration, gained filtrate is through 200 ~ 300 object silica column purification, and gained solid is 4-Trifluoromethyl-1,2-O-Phenylene Diamine.
3. trifluoromethyl according to claim 1 replaces benzo pyrazinoic acid amide syntheti c route step 2, it is characterized in that the concrete steps of described reaction are as follows: by 4-Trifluoromethyl-1,2-O-Phenylene Diamine and oxalic dialdehyde are put in reactor according to the mol ratio of 1:1.2, take potassium tert.-butoxide as alkali, ethanol: water=2:1 is reaction system solvent, back flow reaction at 100 DEG C, TLC plate following response.Reaction 12h, cooling, suction filtration, gained filtrate is through 200 ~ 300 object silica column purification, and gained solid is trifluoromethyl benzo pyrazine.
4. trifluoromethyl according to claim 1 replaces benzo pyrazinoic acid amide syntheti c route step 3, it is characterized in that the concrete steps of described reaction are as follows: trifluoromethyl benzo pyrazine is added drop-wise in the vitriol oil of stirring and forms trifluoromethyl benzo pyrazine vitriol by this reaction, join in 0 DEG C of methane amide after crystal being pulverized after cooling crystallize out in batches, add tertbutyl peroxide and ferrous sulfate reaction 30min simultaneously.Pyrazinoic acid amide is obtained with chloroform extraction after the excessive formic acid of underpressure distillation.Gained material is through 200 ~ 300 object silica column purification, and gained solid is trifluoromethyl benzo pyrazinoic acid amide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631680A (en) * | 2016-12-20 | 2017-05-10 | 江南大学 | Method for synthesizing trifluoromethyl aromatic compounds |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103420927A (en) * | 2013-06-07 | 2013-12-04 | 华中农业大学 | Synthetic method of quinoxaline-2-carboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420927A (en) * | 2013-06-07 | 2013-12-04 | 华中农业大学 | Synthetic method of quinoxaline-2-carboxylic acid |
Non-Patent Citations (3)
| Title |
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| ARTHUR E. HARMS,: "An Efficient Synthesis of 2-Quinoxalinecarboxylic Acid", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| LAINNE E. SEITZ ET AL.,: "Synthesis and Antimycobacterial Activity of Pyrazine and Quinoxaline Derivatives", 《J. MED. CHEM.》 * |
| TODD D. SENECAL ET AL.,: "Room Temperature Aryl Trifluoromethylation via Copper-Mediated Oxidative Cross-Coupling", 《J. ORG. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631680A (en) * | 2016-12-20 | 2017-05-10 | 江南大学 | Method for synthesizing trifluoromethyl aromatic compounds |
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Application publication date: 20150617 |