CN108191863A - A kind of B-carboline of carboxylic acid derivatization and preparation method thereof - Google Patents
A kind of B-carboline of carboxylic acid derivatization and preparation method thereof Download PDFInfo
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- CN108191863A CN108191863A CN201810297562.5A CN201810297562A CN108191863A CN 108191863 A CN108191863 A CN 108191863A CN 201810297562 A CN201810297562 A CN 201810297562A CN 108191863 A CN108191863 A CN 108191863A
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- carboline
- carboxylic acid
- preparation
- acid derivatization
- metal salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of β carbolines of carboxylic acid derivatization, further relate to the preparation method of the β carbolines of the carboxylic acid derivatization, include the following steps：To 6 methyl β carbolines, metal salt catalyst, initiator mixture in, add in organic solvent, be passed through oxygen, after being stirred to react, terminate reaction；Solid crude product is collected in filtering；Solid crude product is further purified by recrystallization or silica gel chromatographic column, obtains product.Technical solution provided by the present invention, reaction condition is mild, the substrate scope of application is wide, can obtain the β carboline derivatives of a large amount of structure diversities.
Description
Technical field
The present invention relates to chemistry and pharmaceutical technology fields more particularly to a kind of B-carboline of carboxylic acid derivatization, and the present invention is also
It is related to the preparation method of the B-carboline.
Background technology
'Beta '-carboline compound is a kind of alkaloid being widely present in nature in terrestrial plant and marine organisms, β-
Carboline compound contains the composition structure of indoles, tryptamines, has extensive bioactivity, and such as antitumor, antiviral, antibacterial resists
Protozoon, antithrombotic, anti-alzheimer syndrome etc..B-carboline class compound is guide's chemical combination of most potential using value
One of object.In recent years, obtained a large amount of B-carboline class compounds by artificial synthesized, however such compound structure-activity relationship
Research be not also very deep.Synthesize the 'Beta '-carboline compound with structure diversity, further explore structure-activity relationship very
It is necessary.
Carboline forms three-membered ring framework structured compound by phenyl ring, pyrrole ring and pyridine ring.It is former according to nitrogen in pyridine ring
The position of son is divided into α, beta, gamma-carboline.Current most of artificial synthesized 'Beta '-carboline compound structure of modification are concentrated mainly on pyrrole
Cough up ring, on pyridine ring, the derivative of this kind of structural modification, such as the structural modification on C1, C3 or N9, anticancer work can be enhanced
Property；Modification on C3 and N9 can reduce toxicity and neurotoxicity；Modification on N2 can enhance cell toxicant simultaneously
Property and acute toxicity.However the 'Beta '-carboline compound of the structural modification on phenyl ring is significantly few very much, the diversity of molecular structure
It is apparent insufficient, cause few to the bioactivity research of this kind of compound.Research and development have abundant various structures on phenyl ring
Property B-carboline class compound, extend carboline class compound library, to find the drug with potential application foreground with important
Meaning.Conventional oxidation alkyl aromatic compound is the method for aromatic carboxylic acid, main to be come using big excessive high-valency metal compound
It completes, such as KMnO4, K2Cr2O7, OsO4, CrO3Deng be easy to causeing environmental pollution.In addition, having for oxidation of alkyl substitution is multiple
The fused ring compound containing aromatic rings, aromatic heterocycle of miscellaneous structure is rarely reported.Research and develop the height chemistry choosing of this kind of compound
The method for oxidation of selecting property, is of great significance.
Invention content
For the problem that existing B-carboline class compound, the structure diversity especially on phenyl ring is insufficient, institute of the present invention
First technical problem to be solved be to provide it is novel it is a kind of Carboxylation B-carboline is carried out on phenyl ring, with Carboxylation
B-carboline is starting material, by the B-carboline to synthesize numerous structure diversities, for bioactivity research, provides molecule
Basis.Second technical problem to be solved by this invention is to provide a kind of Carboxylation on phenyl ring-B-carboline class compound
Preparation method.Method therefor is using the metal salt of catalytic amount as catalyst, using oxygen as oxidant.Wide application range of substrates,
Reaction selectivity is high, and functional group tolerance is strong, reaction condition greenization, and post processing is simple, and yield is high.
In order to solve the above-mentioned technical problem, the present invention is addressed by following technical proposals.
A kind of B-carboline of carboxylic acid derivatization, the B-carboline of the carboxylic acid derivatization have following structure：
Wherein：R is hydrogen, chlorine, bromine or methoxyl group.
The preparation method of the B-carboline of carboxylic acid derivatization involved in the present invention, includes the following steps：To 6- methyl-β-
Carboline, metal salt catalyst, initiator mixture in, add in organic solvent, be passed through oxygen, after being stirred to react, terminate anti-
It should；Solid crude product is collected in filtering；Solid crude product is further purified by recrystallization or silica gel chromatographic column, obtains product.
Preferably, the metal salt catalyst is selected from iron, cobalt, copper, nickel, zinc, the villaumite of manganese, bromide, acetate, sulphur
The one or two of hydrochlorate.
Preferably, the metal salt catalyst is cobalt acetate or cobalt acetate and manganese sulfate dual-component catalyst.
Preferably, the metal salt catalyst dosage is the 1-20mol%, preferably 2-15 of reaction substrate amount
Mol%.
Preferably, the initiator is selected from tert-butyl hydroperoxide (TBHP), n-Hydroxyphthalimide
(NHPI) one kind in.
Preferably, the amount of the initiator is the 1-50mol%, preferably 2-40mol% of reaction substrate amount.
Preferably, the organic solvent is selected from one kind of acetonitrile, acetic acid, halogenated hydrocarbons.
Preferably, the organic solvent is dichloromethane.
Preferably, reaction temperature is 0-80 DEG C, preferably 10-40 DEG C.
Preferably, the reaction time is 1-30 hours, preferably 5-20 hours.
Technical solution provided by the present invention, reaction condition is mild, the substrate scope of application is wide, and reaction selectivity is high,
Functional group tolerance is strong, can obtain the beta-carboline derivatives of a large amount of structure diversities the short period.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are intended merely to the feature and advantage further illustrated the present invention rather than to the claims in the present invention
Limitation.
The preparation method of embodiment in the present invention is as follows：In organic solvent, add in methyl-ss-carboline, catalyst and
Condensing agent reacts certain time at a certain temperature, and crude product is obtained after reaction mixture filtering, crude product through recrystallization or
Product is obtained after chromatography.Embodiment 1-15, methyl-ss-carboline reaction raw materials used, catalyst, initiator, You Jirong
Agent, reaction temperature, reaction time and yield are shown in Table 1.The compound structure of product is shown in Table 2.
Table 1
Table 2
Above as can be seen that B-carboline of carboxylic acid derivatization provided by the present invention and preparation method thereof, reaction condition temperature
It is wide with the substrate scope of application, the beta-carboline derivatives of a large amount of structure diversities can be obtained.
The foregoing description of the disclosed embodiments enables professional and technical personnel in the field to realize or use the present invention.
A variety of modifications of these embodiments will be apparent for those skilled in the art, determine herein
The General Principle of justice can be realized in embodiment without departing from the spirit or scope of the present invention.Thus, this hair
It is bright to be not intended to be limited to the embodiments shown herein, and be to fit to and the principles and novel features disclosed herein
Consistent most wide range.
Claims (10)
1. a kind of B-carboline of carboxylic acid derivatization, which is characterized in that the B-carboline of the carboxylic acid derivatization has following structure：
Wherein：R is hydrogen, chlorine, bromine or methoxyl group.
2. the preparation method of the B-carboline of carboxylic acid derivatization described in claim 1, which is characterized in that include the following steps：To
6- methyl-ss-carbolines, metal salt catalyst, initiator mixture in, add in organic solvent, be passed through oxygen, after being stirred to react,
Terminate reaction；Solid crude product is collected in filtering；Solid crude product is further purified by recrystallization or silica gel chromatographic column, is obtained
Product.
3. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that the metal salt is urged
Agent is selected from the one or two of iron, cobalt, copper, nickel, zinc, the villaumite of manganese, bromide, acetate, sulfate.
4. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 3, which is characterized in that the metal salt is urged
Agent is cobalt acetate or cobalt acetate and manganese sulfate dual-component catalyst.
5. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that the metal salt is urged
Agent dosage is the 1-20mol% of reaction substrate amount.
6. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that the initiator choosing
One kind from tert-butyl hydroperoxide, n-Hydroxyphthalimide.
7. the preparation method of the B-carboline of the carboxylic acid derivatization according to claim 2 or 6, which is characterized in that the initiation
The amount of agent is the 1-50mol% of reaction substrate amount.
8. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that the organic solvent
Selected from acetonitrile, acetic acid, halogenated hydrocarbons one kind.
9. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that reaction temperature 0-
80℃。
10. the preparation method of the B-carboline of carboxylic acid derivatization according to claim 2, which is characterized in that the reaction time is
1-30 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240597A (en) * | 2018-04-04 | 2019-09-17 | 宁波大学 | A kind of B-carboline of amide derivative and preparation method thereof |
| US10947253B2 (en) | 2019-08-05 | 2021-03-16 | Ankh Life Sciences Limited | Fused polycyclic dimers |
| CN115227694A (en) * | 2022-06-07 | 2022-10-25 | 宁波大学 | Application of beta-carboline alkaloid derivative in preparation of medicine for treating or preventing toxoplasmosis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4600715A (en) * | 1983-06-23 | 1986-07-15 | Shering Aktiengesellschaft | Benzodiazepine antagonistic β-carboline derivatives and compositions thereof |
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2018
- 2018-04-04 CN CN201810297562.5A patent/CN108191863A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4600715A (en) * | 1983-06-23 | 1986-07-15 | Shering Aktiengesellschaft | Benzodiazepine antagonistic β-carboline derivatives and compositions thereof |
Non-Patent Citations (3)
| Title |
|---|
| ADITYA KULKARNI等人: "A direct synthesis of b-carbolines via a three-step one-pot domino approach with a bifunctional Pd/C/K-10 catalyst", 《TETRAHEDRON LETTERS》 * |
| 许海峰等: "N-羟基邻苯二甲酰亚胺及其类似物催化的分子氧氧化反应", 《化学进展》 * |
| 邓余等: "天然产物中的β-咔啉生物碱及其生物活性研究进展", 《中草药》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240597A (en) * | 2018-04-04 | 2019-09-17 | 宁波大学 | A kind of B-carboline of amide derivative and preparation method thereof |
| US10947253B2 (en) | 2019-08-05 | 2021-03-16 | Ankh Life Sciences Limited | Fused polycyclic dimers |
| CN115227694A (en) * | 2022-06-07 | 2022-10-25 | 宁波大学 | Application of beta-carboline alkaloid derivative in preparation of medicine for treating or preventing toxoplasmosis |
| CN115227694B (en) * | 2022-06-07 | 2023-09-22 | 宁波大学 | Application of beta-carboline alkaloid derivative in preparation of medicine for treating or preventing toxoplasmosis |
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Application publication date: 20180622 |