CN105315288B - It is a kind of to prepare nafoxidine and the method for pyrazine and isoindole derivatives - Google Patents
It is a kind of to prepare nafoxidine and the method for pyrazine and isoindole derivatives Download PDFInfo
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- CN105315288B CN105315288B CN201510823644.5A CN201510823644A CN105315288B CN 105315288 B CN105315288 B CN 105315288B CN 201510823644 A CN201510823644 A CN 201510823644A CN 105315288 B CN105315288 B CN 105315288B
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- Prior art keywords
- pyrazine
- nafoxidine
- isoindole derivatives
- amino
- ethyls
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of nafoxidine and the preparation method of pyrazine and isoindole derivatives.It is with 1（2 amino-ethyls）Pyrroles and aromatic aldehyde are raw material, and in the presence of acidic, back flow reaction 6~24 hours, nafoxidine can be obtained and pyrazine and isoindole derivatives through simple post processing purge process in organic solvent.Reaction condition of the present invention is gentle, process is simple, simple operation；Gained nafoxidine and pyrazine and isoindole derivatives have potential good bioactivity, it is possible to used as organic synthesis intermediate.
Description
Technical field
The present invention relates to a kind of method for preparing alkaloid, in particular relate to one kind and prepare nafoxidine and pyrazine and different Yin
The method of diindyl derivative.
Background technology
Nafoxidine and pyrazine and isoindole derivatives are a kind of alkaloids with important biomolecule activity, can be as essence
The important intermediate of chemical product is refined, has extensive use in fields such as medicine, agricultural chemicals, coating, photosensitive material, macromolecular materials
On the way, bibliography is shown in Farmaco, Edizione Scientifica, 1975,30,631-632；US 5378846,1995；
J.Med.Chem.1998,41,4118；US 5668283,1997.Pyrroles's parent nucleus is also extremely important in drug research, shows the most
The example of work is the Lipitor (atorvastatin or Lipitor) of the world's most one of well selling medicine, with the good effect of reducing blood lipid,
The parent nucleus skeleton of the medicine just contains pyrroles.The condensation reaction assisted by BTA can prepare the tetrahydrochysene pyrrole of correlation type
Cough up and pyrazines derivatives, bibliography is shown in J.Org.Chem.2002,67,8220.Due to polysubstituted nafoxidine and pyrazine and different
The usual of indole derivatives possesses bioactivity higher, and as the important intermediate of organic synthesis, therefore can often enter
One step develops the efficient preparation method of the analog derivative, significant to new medicament screen.
The content of the invention
It is an object of the invention to provide one kind reaction it is gentle, prepare nafoxidine easily to operate and pyrazine and iso-indoles spread out
Biological method.
The preparation method of nafoxidine of the invention and pyrazine and isoindole derivatives, its step is：With 1- (2- amino second
Base) pyrroles and aromatic aldehyde be raw material, in the presence of acidic, back flow reaction 6~24 hours in organic solvent, by pure
Change process obtains nafoxidine and pyrazine and isoindole derivatives；1- (2- amino-ethyls) pyrroles and aromatic aldehyde and acidic catalyst
Between mol ratio be 1：2~2.2：0.05~0.5；
Reaction equation is：
In formula：R1And R2Selected from H, C1~C5Alkyl or C1~C5Alkoxy.
In the present invention, described acidic catalyst is p-methyl benzenesulfonic acid, benzene sulfonic acid, to ethyl phenenyl azochlorosulfonate acid, trifluoroacetic acid
Or TFMS.
In the present invention, described organic solvent is acetonitrile, tetrahydrofuran, toluene, benzene, dimethylbenzene, methyl tertiary butyl ether(MTBE), 2-
Methyltetrahydrofuran or dichloroethanes.
Synthetic method of the invention has advantages below：
1) reaction condition is gentle；
2) highly versatile is reacted；
3) feed intake and post-process all very simple.
4) reaction initiation material is readily available, and product has diversity.
Specific embodiment
Following examples will be helpful to understand the present invention, but be not limited to present disclosure：
Embodiment 1
With 1- (2- amino-ethyls) pyrroles's (1 mM) and p-tolyl aldehyde (2 mMs) as raw material, to toluene sulphur
In the presence of acid catalyst (0.5 mM), back flow reaction 24 hours in 10 milliliters of tetrahydrofurans, reaction solution is concentrated under reduced pressure into
Dry, the mixture of concentration obtains 10- methyl -8 (p-methylphenyl) -5,6,8,12b- nafoxidines by column chromatography purge process
[2'.1':3,4] and pyrazine [2,1-a] iso-indoles, yield 88%；1H NMR(400MHz,CDCl3)δ7.66(2H),7.23
(2H), 7.12 (2H), 7.05 (2H), 6.38 (d, J=3.7Hz, 1H), 6.01 (d, J=3.7Hz, 1H), 3.98 (2H), 3.89
(d, J=6.6Hz, 2H), 3.82-3.69 (m, 3H), 2.40 (s, 3H), 2.33 (s, 3H) ppm；MS(EI):m/z(M+):314。
Embodiment 2
With 1- (2- amino-ethyls) pyrroles's (1 mM) and P-methoxybenzal-dehyde (2.2 mMs) as raw material, in benzene sulphur
In the presence of acid catalyst (0.05 mM), back flow reaction 12 hours in 10 milliliters of dichloroethanes, reaction solution is full with 20 milliliters
Dry with being concentrated under reduced pressure into after sodium bicarbonate aqueous solution washing, the mixture of concentration obtains 10- methoxies by column chromatography purge process
Base -8 (p-methoxyphenyl) -5,6,8,12b- nafoxidines [2'.1':3,4] and pyrazine [2,1-a] iso-indoles, yield 85%.
Embodiment 3
It is original with (2.0 mMs) of 1- (2- amino-ethyls) -2- N-ethyl pyrrole Ns (1 mM) and P-methoxybenzal-dehyde
Material, in the presence of trifluoroacetic acid catalyst (0.15 mM), reacts 24 hours in 10 milliliters of reflux in toluene, and reaction solution uses 20
It is concentrated under reduced pressure into dry after milliliter saturated sodium bicarbonate aqueous solution washing, the mixture of concentration obtains 3- by column chromatography purge process
Ethyl 10- methoxyl groups -8 (p-methoxyphenyl) -5,6,8,12b- nafoxidines [2'.1':3,4] and pyrazine [2,1-a] different Yin
Diindyl, yield 75%.
Claims (2)
1. the preparation method of a kind of nafoxidine and pyrazine and isoindole derivatives, its step is：With 1- (2- amino-ethyls) pyrrole
It is raw material to cough up with aromatic aldehyde, in the presence of acidic, back flow reaction 6~24 hours in organic solvent, by purifying
Journey obtains nafoxidine and pyrazine and isoindole derivatives；1- (2- amino-ethyls) is between pyrroles and aromatic aldehyde and acidic catalyst
Mol ratio be 1：2~2.2：0.05~0.5；
Reaction equation is：
In formula：R1And R2Selected from H, C1~C5Alkyl or C1~C5Alkoxy；
Described acidic catalyst be p-methyl benzenesulfonic acid, benzene sulfonic acid, to ethyl phenenyl azochlorosulfonate acid, trifluoroacetic acid or TFMS.
2. it is according to claim 1 to prepare nafoxidine and the method for pyrazine and isoindole derivatives, it is characterised in that institute
The organic solvent said is acetonitrile, tetrahydrofuran, toluene, benzene, dimethylbenzene, methyl tertiary butyl ether(MTBE), 2- methyltetrahydrofurans or dichloro
Ethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510823644.5A CN105315288B (en) | 2015-11-24 | 2015-11-24 | It is a kind of to prepare nafoxidine and the method for pyrazine and isoindole derivatives |
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| CN201510823644.5A CN105315288B (en) | 2015-11-24 | 2015-11-24 | It is a kind of to prepare nafoxidine and the method for pyrazine and isoindole derivatives |
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| Publication Number | Publication Date |
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| CN105315288A CN105315288A (en) | 2016-02-10 |
| CN105315288B true CN105315288B (en) | 2017-07-07 |
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| CN201510823644.5A Expired - Fee Related CN105315288B (en) | 2015-11-24 | 2015-11-24 | It is a kind of to prepare nafoxidine and the method for pyrazine and isoindole derivatives |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111057046B (en) * | 2019-12-12 | 2023-06-02 | 安徽师范大学 | Isoindole tetrapyrrole pigment and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5668283A (en) * | 1992-11-12 | 1997-09-16 | Neurogen Corporation | Certain aryl substituted pyrrolopyrazines; a new class of GABA brain receptor ligands |
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