CN109705140A - A kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative - Google Patents
A kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative Download PDFInfo
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- CN109705140A CN109705140A CN201910014229.3A CN201910014229A CN109705140A CN 109705140 A CN109705140 A CN 109705140A CN 201910014229 A CN201910014229 A CN 201910014229A CN 109705140 A CN109705140 A CN 109705140A
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Abstract
The present invention provides a kind of pyridos [2,3-d] [1,3] synthetic method of oxazines derivative, the following steps are included: 3- hydroxymethylpyridine -2- amine and aldehyde are dissolved in organic solvent, 70-90oC stirs 2-3h, by stannous chloride, 2 under oxygen atmosphere, 2,6,6- tetramethyl piperidine -1- oxygen radicals and cyclohexanediamine are added in reaction solution, are back to after reaction, remove organic solvent, residue obtains pyrido [2,3-d] [1,3] oxazines derivative through thin-layer chromatography separation；3- hydroxymethylpyridine -2- amine, aldehyde, stannous chloride, 2,2,6,6- tetramethyl piperidine -1- oxygen radical and cyclohexanediamine molar ratio be 1:1:0.1:0.2:0.2.Method catalytic process of the invention is selectively good, environmentally protective, easy to operate, at low cost, high income, can carry out high-volume synthesis, is suitble to industrial production application.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to a kind of synthesis of pyrido [2,3-d] [1,3] oxazines derivative
Method.
Background technique
Pyrido oxazine compound is a kind of very high heterocyclic compound of activity, research has shown that, such compound can
Used in antibacterial agent, antitumor, analgesia and many aspects such as anti-malarial, DNA rotatory enzyme inhibitor, while having in pesticide field and removing
The effects of grass, desinsection.In recent years, researcher has found that pyrido [1,3] oxazines structure compound is a kind of effective tissue factor
Inhibitor, have significant bioactivity and pharmacological activity, therefore become current region of chemistry one of research hotspot.
Since this kind of compound people research is less, synthetic method also has certain limitation.It uses mostly more expensive
Raw material or reaction condition is more harsh or yield is low, meanwhile, it is unfriendly to environment.Therefore, it is significantly limited
Application industrially.Find one not only economic simple but also environmentally friendly process route be the current research emphasis of researchers.
Pyridine synthesis simultaneously [2,3-d] [1,3] oxazines under 2,2,6,6- tetramethyl piperidine -1- oxygen radical and copper (TEMPO-Cu) catalysis
Class compound method is there is not yet document report.
Summary of the invention
The purpose of the present invention is to the synthesis technology of current pyrido [2,3-d] [1,3] oxazine compound is above-mentioned
Deficiency, and provide a kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative.
A kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative, comprising the following steps:
First 3- hydroxymethylpyridine -2- amine and aldehyde are dissolved in organic solvent, 70-90oC stirs 2-3h, then under oxygen atmosphere
By stannous chloride, 2,2,6,6- tetramethyl piperidine -1- oxygen radicals and cyclohexanediamine are added in reaction solution, are back to reaction
After, organic solvent is removed, residue obtains pyrido [2,3-d] [1,3] oxazines derivative through thin-layer chromatography separation；
Wherein, 3- hydroxymethylpyridine -2- amine, aldehyde, stannous chloride, 2,2,6,6- tetramethyl piperidine -1- oxygen radicals and hexamethylene two
The molar ratio of amine is 1:1:0.1:0.2:0.2.
The organic solvent is acetonitrile or N,N-dimethylformamide.
The thin-layer chromatography is using the mixture of methylene chloride and ethyl acetate as eluant, eluent, wherein methylene chloride and second
The volume ratio of acetoacetic ester is 3-5:1.
The aldehyde is any one in fatty aldehyde, aryl aldehyde and substituted aryl aldehyde.
The invention has the advantages that: the present invention utilizes 2,2,6,6- tetramethyl piperidine -1- oxygen radical and copper (TEMPO-Cu) body
System catalyzes and synthesizes the reaction of 2 substituted pyridines simultaneously [2,3-d] [1,3] oxazines, and compared to known catalysis process, which has
Following advantages: 1) catalyst is cheap, preparation is simple, efficiently；2) catalytic process is selectively good, environmentally protective；3) operation side
Just, at low cost, high income.High-volume synthesis can be carried out, industrial production application is suitble to.
Specific embodiment
The preferred embodiment of invention will be described in detail below.Example be in order to preferably to summary of the invention into
Row, is not that summary of the invention is only limitted to example.Nonessential modifications and adaptations according to summary of the invention to embodiment, still fall within
Invention scope.
The general formula of reaction in the embodiment of the present invention is as follows:
R=fatty aldehyde, aryl aldehyde or substituted aryl aldehyde.
Embodiment one:
The synthesis of 2- phenylpyridine simultaneously [2,3-d] [1,3] oxazines
4.96g(40mmol is added in dry round-bottomed flask) 3- hydroxymethylpyridine -2- amine and 4.24g(40mmol) benzene first
Aldehyde, 100mL acetonitrile stir 2h as solvent at 80oC, then under oxygen atmosphere by 0.4g(4mmol) stannous chloride,
1.25g(8mmol) 2,2,6,6- tetramethyl piperidine -1- oxygen radical (TEMPO), 0.91g(8mmol) cyclohexanediamine is added to instead
It answers in solution, is heated to reflux, after reaction stops, being neutralized with anhydrous sodium sulfite, filter to obtain solid, crude product thin layer chromatography
(methylene chloride: ethyl acetate=3-5:1) separates to obtain brown solid 2- phenylpyridine simultaneously [2,3-d] [1,3] oxazines, fusing point:
183-184.2ºC.Yield (yield): 8.1g(96.5%).Characterize data:1HNMR(400 MHz,DMSO)δ:8.52(s, 1H),
8.22(s,1H),7.93 (s,2H),7.54 (s,3H),7.29 (s,1H),4.86 (m,2H), ppm. EI-MS (m/z):
210。
Embodiment two:
2-(4- methoxyl group) phenylpyridine simultaneously [2,3-d] [1,3] oxazines synthesis
4.96g(40mmol is added in dry round-bottomed flask) 3- hydroxymethylpyridine -2- amine and 5.44g(40mmol) to methoxy
Benzaldehyde, 100mL acetonitrile stir 2h as solvent at 80oC, then by 0.4g(4mmol) protochloride under oxygen atmosphere
Copper, 1.25g(8mmol) 2,2,6,6- tetramethyl piperidine -1- oxygen radicals (TEMPO), 0.91g(8mmol) cyclohexanediamine addition
It into reaction solution, is heated to reflux, after reaction stops, being neutralized with sodium sulfite, filter to obtain solid, crude product thin layer chromatography
(methylene chloride: ethyl acetate=3-5:1) separates to obtain light yellow solid 2-(4- methoxyl group) phenylpyridine simultaneously [1,3] [2,3-d]
Oxazines, fusing point: 168.6-169.3oC. yield (yield): 9.2g(95.7%).Characterize data:1HNMR (400 MHz,DMSO)
δ:9.12(s,1H),8.78(s,2H),8.31(s,1H),8.16(s,1H),7.78(m,2H),4.92(s,2H),3.86(s,
3H). EI-MS (m/z):240。
Embodiment three:
2-(4- fluorine) phenylpyridine simultaneously [2,3-d] [1,3] oxazines synthesis
4.96g(40mmol is added in dry round-bottomed flask) 3- hydroxymethylpyridine -2- amine and 4.96g(40mmol) to fluorobenzene
Formaldehyde, 100mL acetonitrile stir 2h as solvent at 80oC, then under oxygen atmosphere by 0.4g(4mmol) stannous chloride,
1.25g(8mmol) 2,2,6,6- tetramethyl piperidine -1- oxygen radical (TEMPO), 0.91g(8mmol) cyclohexanediamine is added to instead
It answers in solution, is heated to reflux, after reaction stops, being neutralized with sodium sulfite, filter to obtain solid, crude product thin layer chromatography (two
Chloromethanes: ethyl acetate=3-5:1) separate to obtain light yellow solid 2-(4- fluorine) phenylpyridine simultaneously [2,3-d] [1,3] oxazines, it melts
Point: 171.9-172.5oC.Yield (yield): 8.86g(97.2%).Characterize data:1HNMR (400 MHz,DMSO)δ:8.86
(s,1H),8.37(s,1H),7.89(s,2H),7.48(s,2H),7.31(s,1H),4.95(m,2H),ppm.EI-MS (m/
z):228。
Claims (4)
1. a kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative, it is characterised in that the following steps are included:
First 3- hydroxymethylpyridine -2- amine and aldehyde are dissolved in organic solvent, 70-90oC stirs 2-3h, then under oxygen atmosphere
By stannous chloride, 2,2,6,6- tetramethyl piperidine -1- oxygen radicals and cyclohexanediamine are added in reaction solution, are back to reaction
After, organic solvent is removed, residue obtains pyrido [2,3-d] [1,3] oxazines derivative through thin-layer chromatography separation；
Wherein, 3- hydroxymethylpyridine -2- amine, aldehyde, stannous chloride, 2,2,6,6- tetramethyl piperidine -1- oxygen radicals and hexamethylene two
The molar ratio of amine is 1:1:0.1:0.2:0.2.
2. a kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative according to claim 1, feature exist
In the organic solvent be acetonitrile or N,N-dimethylformamide.
3. a kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative according to claim 1, feature exist
In the thin-layer chromatography using the mixture of methylene chloride and ethyl acetate as eluant, eluent, wherein methylene chloride and ethyl acetate
Volume ratio is 3-5:1.
4. a kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative according to claim 1, feature exist
In the aldehyde be fatty aldehyde, aryl aldehyde and substituted aryl aldehyde in any one.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240604A (en) * | 2019-07-08 | 2019-09-17 | 荆楚理工学院 | A kind of synthetic method of pyrido oxazole derivatives |
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| WO2011047432A1 (en) * | 2009-10-22 | 2011-04-28 | Fibrotech Therapeutics Pty Ltd | Fused ring analogues of anti-fibrotic agents |
| CN106831632A (en) * | 2017-01-24 | 2017-06-13 | 浙江工业大学 | A kind of benzo oxazinyl compound catalysis oxidation synthetic methods of 4H 3,1 |
| CN108558870A (en) * | 2018-05-14 | 2018-09-21 | 荆楚理工学院 | The method for synthesizing 2 aryl-pyridines simultaneously [2,3-d] pyrimidine derivatives |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011047432A1 (en) * | 2009-10-22 | 2011-04-28 | Fibrotech Therapeutics Pty Ltd | Fused ring analogues of anti-fibrotic agents |
| CN106831632A (en) * | 2017-01-24 | 2017-06-13 | 浙江工业大学 | A kind of benzo oxazinyl compound catalysis oxidation synthetic methods of 4H 3,1 |
| CN108558870A (en) * | 2018-05-14 | 2018-09-21 | 荆楚理工学院 | The method for synthesizing 2 aryl-pyridines simultaneously [2,3-d] pyrimidine derivatives |
Non-Patent Citations (2)
| Title |
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| BING HAN，等: "CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic Oxidative Synthesis of 2-Substituted Quinazolines and 4H-3,1-Benzoxazines", 《J. ORG. CHEM.》 * |
| ZHONGYAN CHEN，等: "Unexpected Copper-Catalyzed Cascade Synthesis of Quinazoline Derivatives", 《J. ORG. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240604A (en) * | 2019-07-08 | 2019-09-17 | 荆楚理工学院 | A kind of synthetic method of pyrido oxazole derivatives |
| CN110240604B (en) * | 2019-07-08 | 2021-04-16 | 荆楚理工学院 | Synthesis method of pyridooxazole derivative |
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Application publication date: 20190503 |