CN105315288A - Method for preparing nafoxidine-pyrazine-isoindole derivative - Google Patents
Method for preparing nafoxidine-pyrazine-isoindole derivative Download PDFInfo
- Publication number
- CN105315288A CN105315288A CN201510823644.5A CN201510823644A CN105315288A CN 105315288 A CN105315288 A CN 105315288A CN 201510823644 A CN201510823644 A CN 201510823644A CN 105315288 A CN105315288 A CN 105315288A
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- CN
- China
- Prior art keywords
- pyrazine
- pyrrolidine
- nafoxidine
- acid
- ethyl
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 0 Cc1ccc(*)cc1 Chemical compound Cc1ccc(*)cc1 0.000 description 4
- HPDIRFBJYSOVKW-UHFFFAOYSA-N NCC[n]1cccc1 Chemical compound NCC[n]1cccc1 HPDIRFBJYSOVKW-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- 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)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The method discloses a method for preparing a nafoxidine-pyrazine-isoindole derivative. The nafoxidine-pyrazine-isoindole derivative can be obtained by conducting a reflux reaction in organic solvent for 6-24 hours under the existence of an acid catalyst with 1-(2-aminoethyl) pyrrole and aromatic aldehyde as raw materials and conducting the simple postprocessing purification process. The reaction condition is gentle, the process is simple, operation is convenient, and the prepared nafoxidine-pyrazine-isoindole derivative has potential good bioloigcla activity, and can be used as an organic synthesis intermediate.
Description
Technical field
The present invention relates to one and prepare alkaloidal method, relate to specifically and a kind ofly prepare Pyrrolidine and pyrazine the method for isoindole derivatives.
Background technology
Pyrrolidine pyrazine isoindole derivatives is a kind of alkaloid with important biomolecule activity, can as the important intermediate of fine chemical product, purposes is widely had in fields such as medicine, agricultural chemicals, coating, sensitive materials, macromolecular materials, reference is shown in Farmaco, EdizioneScientifica, 1975,30,631-632; US5378846,1995; J.Med.Chem.1998,41,4118; US5668283,1997.Pyrroles's parent nucleus is also extremely important in drug research, and the most significant example is the Lipitor (atorvastatin or Lipitor) of one of the most well selling medicine in the world, and have the good effect of reducing blood-fat, the parent nucleus skeleton of this medicine is just containing pyrroles.The condensation reaction of being assisted by benzotriazole can prepare the Pyrrolidine of correlation type and pyrazines derivatives, and reference is shown in J.Org.Chem.2002, and 67,8220.Due to polysubstituted Pyrrolidine and pyrazine isoindole derivatives usually have higher biological activity, and often can as the important intermediate of organic synthesis, therefore the efficient preparation method of this analog derivative is developed further, significant to new medicament screen.
Summary of the invention
The object of this invention is to provide a kind of reaction temperature and, easy and simple to handle prepare Pyrrolidine and pyrazine the method for isoindole derivatives.
Pyrrolidine of the present invention pyrazine the preparation method of isoindole derivatives, the steps include: with 1-(2-amino-ethyl) pyrroles and aromatic aldehyde as raw material, in the presence of acidic, back flow reaction 6 ~ 24 hours in organic solvent, obtains Pyrrolidine and pyrazine isoindole derivatives through purge process; 1-(2-amino-ethyl) pyrroles and the mol ratio between aromatic aldehyde and an acidic catalyst are 1:2 ~ 2.2:0.05 ~ 0.5;
Reaction formula is:
In formula: R
1and R
2be selected from H, C
1~ C
5alkyl or C
1~ C
5alkoxyl group.
In the present invention, said an acidic catalyst be p-methyl benzenesulfonic acid, Phenylsulfonic acid, to ethyl phenenyl azochlorosulfonate acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
In the present invention, said organic solvent is acetonitrile, tetrahydrofuran (THF), toluene, benzene, dimethylbenzene, methyl tertiary butyl ether, 2-methyltetrahydrofuran or ethylene dichloride.
Synthetic method of the present invention has the following advantages:
1) reaction conditions is gentle;
2) highly versatile is reacted;
3) feed intake and aftertreatment all very simple.
4) react starting raw material easily to obtain, product has diversity.
Embodiment
Following examples will contribute to understanding the present invention, but be not limited to content of the present invention:
Embodiment 1
With 1-(2-amino-ethyl) pyrroles (1 mmole) and p-tolyl aldehyde (2 mmole) for raw material, under Catalyzed by p-Toluenesulfonic Acid agent (0.5 mmole) exists, back flow reaction 24 hours in 10 milliliters of tetrahydrofuran (THF)s, reaction solution is evaporated to dry, concentrated mixture obtains 10-methyl-8 (p-methylphenyl)-5 through column chromatography purification process, 6,8,12b-Pyrrolidine [2'.1':3,4] and pyrazine [2,1-a] isoindole, productive rate 88%;
1hNMR (400MHz, CDCl
3) δ 7.66 (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-ethyl) pyrroles (1 mmole) and aubepine (2.2 mmole) for raw material, under Phenylsulfonic acid catalyzer (0.05 mmole) exists, back flow reaction 12 hours in 10 milliliters of ethylene dichloride, reaction solution is dry with being evaporated to after 20 milliliters of saturated sodium bicarbonate aqueous solution washings, concentrated mixture obtains 10-methoxyl group-8 (p-methoxyphenyl)-5 through column chromatography purification process, 6,8,12b-Pyrrolidine [2'.1':3,4] and pyrazine [2,1-a] isoindole, productive rate 85%.
Embodiment 3
With 1-(2-amino-ethyl)-2-N-ethyl pyrrole N-(1 mmole) and aubepine (2.0 mmole) for raw material, under trifluoroacetic acid catalyzer (0.15 mmole) exists, 24 hours are reacted 10 milliliters of reflux in toluene, reaction solution is dry with being evaporated to after 20 milliliters of saturated sodium bicarbonate aqueous solution washings, concentrated mixture obtains 3-ethyl 10-methoxyl group-8 (p-methoxyphenyl)-5 through column chromatography purification process, 6,8,12b-Pyrrolidine [2'.1':3,4] and pyrazine [2,1-a] isoindole, productive rate 75%.
Claims (3)
1. a Pyrrolidine pyrazine the preparation method of isoindole derivatives, the steps include: with 1-(2-amino-ethyl) pyrroles and aromatic aldehyde be raw material, in the presence of acidic, back flow reaction 6 ~ 24 hours in organic solvent, obtains Pyrrolidine by purge process and pyrazine isoindole derivatives; 1-(2-amino-ethyl) pyrroles and the mol ratio between aromatic aldehyde and an acidic catalyst be 1:2 ~ 2.2:0.05 ~ 0.5;
Reaction formula is:
；
In formula: R
1and R
2be selected from H, C
1~ C
5alkyl or C
1~ C
5alkoxyl group.
2. according to claim 1ly prepare Pyrrolidine and pyrazine the method for isoindole derivatives, it is characterized in that said an acidic catalyst be p-methyl benzenesulfonic acid, Phenylsulfonic acid, to ethyl phenenyl azochlorosulfonate acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
3. according to claim 1ly prepare Pyrrolidine and pyrazine the method for isoindole derivatives, it is characterized in that said organic solvent is acetonitrile, tetrahydrofuran (THF), toluene, benzene, dimethylbenzene, methyl tertiary butyl ether, 2-methyltetrahydrofuran or ethylene dichloride.
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 |
Applications Claiming Priority (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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105315288A true CN105315288A (en) | 2016-02-10 |
| CN105315288B CN105315288B (en) | 2017-07-07 |
Family
ID=55243682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105315288B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057046A (en) * | 2019-12-12 | 2020-04-24 | 安徽师范大学 | Isoindole tetrapyrrole pigment and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5668283A (en) * | 1992-11-12 | 1997-09-16 | Neurogen Corporation | Certain aryl substituted pyrrolopyrazines; a new class of GABA brain receptor ligands |
-
2015
- 2015-11-24 CN CN201510823644.5A patent/CN105315288B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5668283A (en) * | 1992-11-12 | 1997-09-16 | Neurogen Corporation | Certain aryl substituted pyrrolopyrazines; a new class of GABA brain receptor ligands |
Non-Patent Citations (4)
| Title |
|---|
| AKHILESH K. VERMA等: "Lewis Acid-Catalyzed Selective Synthesis of Diversely Substituted Indolo- and Pyrrolo[1,2-a]quinoxalines and Quinoxalinones by Modified Pictet–Spengler Reaction", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| ALAN R. KATRITZKY等: "Convenient syntheses of dihydropyrrolo[2",1":3,4]pyrazino- and dihydropyrrolo[2",1":3,4][1,4]diazepino-[2,1-a]isoindolones", 《TETRAHEDRON LETTERS》 * |
| NITIN T. PATIL等: "Relay Catalytic Branching Cascade: A Technique to Access Diverse Molecular Scaffolds", 《ANGEW. CHEM. INT. ED.》 * |
| OTHMAN, MOHAMED等: "Quinoxalines, benzodiazepines and benzodiazocines fused to pyrrole and isoindole via N-acyliminium ion aromatic cyclization", 《HETEROCYCLES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057046A (en) * | 2019-12-12 | 2020-04-24 | 安徽师范大学 | Isoindole tetrapyrrole pigment and preparation method thereof |
| CN111057046B (en) * | 2019-12-12 | 2023-06-02 | 安徽师范大学 | Isoindole tetrapyrrole pigment and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105315288B (en) | 2017-07-07 |
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Granted publication date: 20170707 Termination date: 20201124 |