CN105503737B - A kind of method of no catalyst preparation benzimidazole or benzothiazole compound - Google Patents
A kind of method of no catalyst preparation benzimidazole or benzothiazole compound Download PDFInfo
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- CN105503737B CN105503737B CN201610047099.XA CN201610047099A CN105503737B CN 105503737 B CN105503737 B CN 105503737B CN 201610047099 A CN201610047099 A CN 201610047099A CN 105503737 B CN105503737 B CN 105503737B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
Abstract
A kind of method of no catalyst preparation benzimidazole or benzothiazole compound, belongs to technical field of organic synthesis.This method is in water and under air conditions, is reacted with cyclohexadione compounds using o-phenylenediamine class or adjacent aminobenzene sulfur alcohol compound and is efficiently prepared benzimidazole or benzothiazole compound.The characteristics of this method is without catalyst and any additive, it can react in single water phase, the use of catalyst, various additives and toxic organic solvents is avoided, reaction system is green, efficient, is the excellent system for preparing benzimidazole and benzothiazole compound.
Description
Technical field
The present invention relates to a kind of benzimidazoles or benzene in water, under air conditions, without catalyst, without any additive
And the preparation method of thiazole compound, belong to technical field of organic synthesis.
Background technology
Benzimidazole and benzothiazole compound are important pharmaceutical intermediate, have extensively in pesticide, medicine and other fields
General application, for synthesize anti HIV-1 virus, anticancer, antibacterial and plant virus etc. (Chin. J. Pestic. 2000,39,
1; Pharm. Chem. J. 2000, 34, 353; Bioorg. Med. Chem. Lett. 2002, 12, 3275;
Med. Chem. Lett. 2003, 13, 471; Bioorg. Med. Chem. 2006, 14, 6106; J. Med.
Chem. 2012, 55, 2981).O-phenylenediamine class compound or adjacent aminobenzene sulfur alcohol compound and cyclohexadione compounds
Reaction is synthesizing benzimidazole and a kind of effective ways of benzothiazole compound (Org. Lett. 2014,16,764; J.
Heterocyclic Chem. 2005, 42, 1001).Benzene is prepared with o-phenylenediamine class compound in patent CN103910682A
And imidazoles, using Bronsted acid as catalyst, organic solvent is as solvent.I.e. the reaction system need to use catalysis in the prior art
The problems such as agent, organic solvent need the special reactions condition such as microwave, and the reaction time is long.Therefore, develop environmental-friendly
Efficient, the economic response system carried out in reaction medium has important answer to prepare benzimidazole and benzothiazole compound
With value.
Invention content
To solve problems of the prior art, the object of the present invention is to provide a kind of preparations efficiently, green, economic
The preparation method of benzimidazole or benzothiazole compound.
The technical solution adopted by the present invention is：A kind of no catalyst preparation benzimidazole or benzothiazole compound
Method, its reaction route are：
Wherein, R1=-NO2,-H ,-OCH3,-Cl ,-Br ,-CH3,-C2H5；R2=-CH3Or-C2H5；R3=-CH3,-C2H5Or-
OC2H5；X=NH or S；
The preparation method includes the following steps：
（1）Under air conditions, o-phenylenediamine class or adjacent aminobenzene sulfur alcohol compound, cyclohexadione compounds and water are added
Enter in reaction bulb, the o-phenylenediamine class or the molar ratio of adjacent aminobenzene sulfur alcohol compound and cyclohexadione compounds are 1：1.2-
2；The ratio of the cyclohexadione compounds and water is 0.75mmol：（2-5）mL；
（2）It is reacted 1.5 ~ 6 hours at 100 DEG C, reaction process is tracked with thin-layered chromatography；
（3）After reaction, saturated salt solution is added in, reaction mixture is extracted with ethyl acetate 3 times, merges organic
Phase, concentration, uses column chromatography, obtains benzimidazoles compound or benzothiazole compound.
Successively by 0.5 mmol o-phenylenediamines class or adjacent aminobenzene sulfur alcohol compound, 0.75 mmol cyclohexadione compounds
And 2 mL water add in reaction bulb, reacted 1.5 ~ 6 hours at 100 DEG C, track reaction process with thin-layered chromatography, reaction terminates
Afterwards, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate, merges organic phase, and column is used in concentration
Chromatography obtains benzimidazole or benzothiazole compound.The o-phenylenediamine class compound is selected from o-phenylenediamine, 4- methoxies
Base o-phenylenediamine, 3,4- diaminotoluenes, 4- chlorine o-phenylenediamine or 4-nitro-o-phenylenediamine.Neighbour's aminobenzene thio-alcohol chemical combination
Object is selected from adjacent amino benzenethiol or 2- amino -4- chlorobenzenethiols.The cyclohexadione compounds are selected from acetylacetone,2,4-pentanedione, bis- heptanone of 3,5-
Or ethyl acetoacetate.
The beneficial effects of the invention are as follows：This method is in water and under air conditions, using o-phenylenediamine class or adjacent amino
Benzenethiol class compound is reacted with cyclohexadione compounds efficiently prepares benzimidazole or benzothiazole compound.Water is used in this method
Instead of the organic solvent in existing method, without catalyst and any additive, it can react, keep away in single water phase
The use of catalyst, various additives and toxic organic solvents is exempted from, reaction system is green, efficient, and the yield of the reaction
Height is the excellent system for preparing benzimidazole and benzothiazole compound.This method mild condition, it is easy to operate, rapid reaction,
Efficiently, there is significant prospects for commercial application.
Specific embodiment
Embodiment 1 synthesizes 2- tolimidazoles
Successively by 0.5 mmol o-phenylenediamines, 0.75 mmol acetylacetone,2,4-pentanediones, 2 mL water are added in reaction bulb, at 100 DEG C
Reaction 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate, is closed
And organic phase, concentration, column chromatography for separation obtain 2- tolimidazoles, separation yield 98%.
Embodiment 2 synthesizes 2- tolimidazoles
Successively by 0.5 mmol o-phenylenediamines, 0.75 mmol acetylacetone,2,4-pentanediones, 5 mL water are added in reaction bulb, at 100 DEG C
Reaction 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate, is closed
And organic phase, concentration, column chromatography for separation obtain 2- tolimidazoles, separation yield 96%.
Embodiment 3 synthesizes 2- tolimidazoles
Successively by 0.5 mmol o-phenylenediamines, 1.0 mmol acetylacetone,2,4-pentanediones, 2 mL water are added in reaction bulb, anti-at 100 DEG C
It answers 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate, is merged
Organic phase, concentration, column chromatography for separation obtain 2- tolimidazoles, separation yield 98%.
Embodiment 4 synthesizes 2- tolimidazoles
Successively by 0.5 mmol o-phenylenediamines, 0.6 mmol acetylacetone,2,4-pentanediones, 2 mL water are added in reaction bulb, anti-at 100 DEG C
It answers 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate, is merged
Organic phase, concentration, column chromatography for separation obtain 2- tolimidazoles, separation yield 95%.
Embodiment 5 synthesizes 2- ethyl benzo imidazoles
0.5 mmol o-phenylenediamines, 0.75 mmol 3, bis- heptanone of 5- and 2 mL water are added in reaction bulb successively, 100
DEG C reaction 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted 3 times with 15 mL of ethyl acetate,
Merge organic phase, concentration, column chromatography for separation obtains 2- ethyl benzo imidazoles, separation yield 96%.
Embodiment 6 synthesizes 2- tolimidazoles
0.5 mmol o-phenylenediamines, 0.75 mmol ethyl acetoacetates and 2 mL water are added in reaction bulb successively,
100 DEG C are reacted 1.5 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted with 15 mL of ethyl acetate
3 times, merge organic phase, concentration, column chromatography for separation obtains 2- tolimidazoles, separation yield 94%.
Embodiment 7 synthesizes 6- methoxyl group -2- methyl-1 H- benzimidazoles
0.5 mmol 4- methoxyl group o-phenylenediamines, 0.75 mmol acetylacetone,2,4-pentanediones and 2 mL water are added in into reaction bulb successively
In, it is reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture ethyl acetate 15 are added in
ML is extracted 3 times, merges organic phase, concentration, and column chromatography for separation obtains 6- methoxyl group -2- methyl-1 H- benzimidazoles, separation yield
83%。
Embodiment 8 synthesizes 6- methoxyl group -2- ethyl -1H- benzimidazoles
0.5 mmol 4- methoxyl group o-phenylenediamines, 0.75 mmol 3, bis- heptanone of 5- and 2 mL water are added in into reaction successively
In bottle, reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture ethyl acetate 15 are added in
ML is extracted 3 times, merges organic phase, concentration, and column chromatography for separation obtains 6- methoxyl group -2- ethyl -1H- benzimidazoles, separation yield
80%。
Embodiment 9 synthesizes 6- methoxyl group -2- methyl-1 H- benzimidazoles
0.5 mmol 4- methoxyl group o-phenylenediamines, 0.75 mmol ethyl acetoacetates and 2 mL water are added in instead successively
It answers in bottle, is reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture ethyl acetate are added in
15 mL are extracted 3 times, merge organic phase, concentration, and column chromatography for separation obtains 6- methoxyl group -2- methyl-1 H- benzimidazoles, and separation is received
Rate 96%.
Embodiment 10 synthesizes 6- methyl -2- methyl-1 H- benzimidazoles
0.5 mmol 3,4- diaminotoluenes, 0.75 mmol acetylacetone,2,4-pentanediones and 2 mL water are added in reaction bulb successively,
It is reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted with 15 mL of ethyl acetate
It takes 3 times, merges organic phase, concentration, column chromatography for separation obtains 6- methyl -2- methyl-1 H- benzimidazoles, separation yield 95%.
Embodiment 11 synthesizes 6- methyl -2- ethyl -1H- benzimidazoles
0.5 mmol 3,4- diaminotoluenes, 0.75 mmol 3, bis- heptanone of 5- and 2 mL water are added in into reaction bulb successively
In, it is reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture ethyl acetate 15 are added in
ML is extracted 3 times, merges organic phase, concentration, and column chromatography for separation obtains 6- methyl -2- ethyl -1H- benzimidazoles, separation yield
98%。
Embodiment 12 synthesizes 6- methyl -2- methyl-1 H- benzimidazoles
0.5 mmol 3,4- diaminotoluenes, 0.75 mmol ethyl acetoacetates and 2 mL water are added in into reaction successively
In bottle, reacted 1.5 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture ethyl acetate 15 are added in
ML is extracted 3 times, merges organic phase, concentration, and column chromatography for separation obtains 6- methyl -2- methyl-1 H- benzimidazoles, separation yield
94%。
Embodiment 13 synthesizes 2- methylbenzothiazoles
0.5 mmol neighbour's amino benzenethiol, 0.75 mmol acetylacetone,2,4-pentanediones and 2 mL water are added in reaction bulb successively,
100 DEG C are reacted 2 hours.After reaction, 10 mL saturated salt solutions are added in, reaction mixture extracts 3 with 15 mL of ethyl acetate
It is secondary, merge organic phase, concentration, column chromatography for separation obtains 2- methylbenzothiazoles, separation yield 89%.
Embodiment 14 synthesizes 2- ethyl-benzothiazoles
0.5 mmol neighbour's amino benzenethiol, 0.75 mmol 3, bis- heptanone of 5- and 2 mL water are added in reaction bulb successively,
It is reacted 2 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions are added in, reaction mixture is extracted with 15 mL of ethyl acetate
3 times, merge organic phase, concentration, column chromatography for separation obtains 2- ethyl-benzothiazoles, separation yield 90%.
Embodiment 15 synthesizes 2- methylbenzothiazoles
0.5 mmol neighbour's amino benzenethiol, 0.75 mmol ethyl acetoacetates and 2 mL water are added in into reaction bulb successively
In, it is reacted 2 hours at 100 DEG C.After reaction, 10 mL saturated salt solutions, reaction mixture 15 mL of ethyl acetate are added in
Extraction 3 times, merges organic phase, concentration, and column chromatography for separation obtains 2- methylbenzothiazoles, separation yield 93%.
The above content is combine optimal technical scheme to the further description of the invention done, it is impossible to assert the present invention's
Specific implementation is only limitted to these explanations.For general technical staff of the technical field of the invention, the present invention is not being departed from
Design under the premise of, can also make it is simple deduce and replace, should all be considered as protection scope of the present invention.
Claims (1)
- A kind of 1. method of no catalyst preparation benzimidazoles compound, which is characterized in that include the following steps：Successively will 0.5mmol o-phenylenediamines, 0.75mmol acetylacetone,2,4-pentanediones, 2mL water are added in reaction bulb, are reacted 2 hours at 100 DEG C；Reaction terminates Afterwards, 10mL saturated salt solutions are added in, reaction mixture is extracted 3 times with ethyl acetate 15mL, merges organic phase, concentration, column chromatography Isolated 2- tolimidazoles.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1454891A (en) * | 2003-05-26 | 2003-11-12 | 北京理工大学 | Benzimidazole and its derivative synthetic method |
| AU2009332651A2 (en) * | 2008-12-26 | 2012-05-03 | Glenmark Pharmaceuticals, S.A. | Fused imidazole derivatives as TRPV3 antagonist |
| CN103483266A (en) * | 2013-08-23 | 2014-01-01 | 广东东硕科技有限公司 | Synthesis method of 2-substituted benzimidazole compound |
| CN103910682A (en) * | 2013-11-28 | 2014-07-09 | 大连理工大学 | Preparation method of benzimidazole compound based on o-phenylenediamine cyclization |
-
2016
- 2016-01-25 CN CN201610047099.XA patent/CN105503737B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1454891A (en) * | 2003-05-26 | 2003-11-12 | 北京理工大学 | Benzimidazole and its derivative synthetic method |
| AU2009332651A2 (en) * | 2008-12-26 | 2012-05-03 | Glenmark Pharmaceuticals, S.A. | Fused imidazole derivatives as TRPV3 antagonist |
| CN103483266A (en) * | 2013-08-23 | 2014-01-01 | 广东东硕科技有限公司 | Synthesis method of 2-substituted benzimidazole compound |
| CN103910682A (en) * | 2013-11-28 | 2014-07-09 | 大连理工大学 | Preparation method of benzimidazole compound based on o-phenylenediamine cyclization |
Non-Patent Citations (2)
| Title |
|---|
| Reaction of 1,3-Dicarbonyl Compounds with o-Phenylenediamine or 3,3"-Diaminobenzidine in Water or under Solvent-free Conditions via Microwave Irradiation;Zhong-Xia Wang，等;《J. Heterocyclic Chem.》;20050831;第42卷;第1001-1005页 * |
| Zhongwen Li，等.Metal- and Oxidant-Free Synthesis of Quinazolinones fromβ‑Ketoesters with o‑Aminobenzamides via Phosphorous Acid-Catalyzed Cyclocondensation and Selective C−C Bond Cleavage.《The Journal of Organic Chemistry》.2015,第80卷第9392-9400页. * |
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