CN103724276A - Novel method for preparing benzimidazole compounds from nitroaniline - Google Patents
Novel method for preparing benzimidazole compounds from nitroaniline Download PDFInfo
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- CN103724276A CN103724276A CN201310677233.0A CN201310677233A CN103724276A CN 103724276 A CN103724276 A CN 103724276A CN 201310677233 A CN201310677233 A CN 201310677233A CN 103724276 A CN103724276 A CN 103724276A
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- bromo
- bromine
- methyl
- phenylene diamine
- nitroanilines
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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
Abstract
The invention discloses a method for preparing benzimidazole compounds from nitroaniline. The method is characterized in that o-phenylenediamine is used as a raw material, and the NBS bromination method is adopted to obtain 4-bromo-2-nitro aniline; 4-bromo-2-nitro aniline is reduced to 4-bromo-1,2-benzenediamine via a special reducing agent, namely sodium metabisulfite, and 4-bromo-1,2-benzenediamine and formic acid are subjected to condensation reaction to obtain 5-bromobenzimidazole. The method has the advantages that on the basis of the traditional benzimidazole synthesis process, a novel method for reduction of 4-bromo-2-nitro aniline is developed, the reduction cost is relatively low, the moderate reduction is realized, fewer by-products are produced, the special reducing agent enables Br- not to be separated easily compared with the common strong reducing agents, such as Pd-C and Fe/HCl. The method has the advantages of low cost, high yield, high purity and high quality of products.
Description
Technical field
The present invention relates to a kind of novel method of being prepared benzimidazoles compound by N-methyl-p-nitroaniline.
Background technology
The bromo-2-N-methyl-p-nitroaniline of 4-, mainly as dyestuff intermediate and synthetic photograph anti-foggant, also for the mensuration of micro iodine compound, the production of pesticide carbendazim etc., is also the important source material of Benzotriazole Ultraviolet Stabilizer simultaneously.
4-bromine O-Phenylene Diamine is a kind of very important fine chemicals, can be used as analytical reagent uses, can also be for the preparation of the benzoglyoxaline of various different purposes and quinoline compound, this two compounds has a wide range of applications at aspects such as medicine, agricultural chemicals and superpolymer.
The synthetic of 4-bromine O-Phenylene Diamine mainly followed following two reaction schemes: wherein a reaction scheme is that 4-bromine O-Phenylene Diamine is by being obtained by o-Nitraniline bromination and reduction.There is following defect in this route: first easily obtain two-bromo nitrobenzene amine by product during bromination, and secondly conventional during reduction or make reductive agent, need to be with a large amount of organic solvents when 4-bromine O-Phenylene Diamine is separated from reductive agent.An other reaction scheme be bromine O-Phenylene Diamine by O-Phenylene Diamine in acetic acid-acetic anhydride bromination subsequently hydrolyzable bromine for Acetanilide, make.In conjunction with two kinds of methods; use acetic acid-acetic anhydride bromination o-Nitraniline can reduce the generation of by product; hydrolyzable bromine obtains the bromo-2-N-methyl-p-nitroaniline of 4-that productive rate is high after for acidylate oil of mirbane; re-use the reductive agent that reductibility is moderate; as iron powder; the transition-metal catalysts such as Pd/C, just can obtain 4-bromine O-Phenylene Diamine.Compared with transition-metal catalyst class reductive agent, Na
2s
2o
4class reductive agent low price, also relatively simple to the structural requirement of initiator, the easy purifying of product, productive rate is higher, in this way has larger practicality.
Benzimidazoles compound is a kind of heterogeneous ring compound that contains 2 nitrogen-atoms, there is special proton and accept performance and conjugate acid and base performance, active centre function at occurring in nature as many enzymes, many important biochemical reactions have been participated in, vital movement is played a very important role, there is significant biological activity.Its derivative is widely used in radiopharmaceuticals as part, also has higher anti-inflammatory activity.Benzimidazoles compound also can be used as pharmaceutical intermediate, the mycocide of the anthelmintic drug of people, animal and both citrus fruit, and fruit antistaling agent.Its some metal complexes has sterilization, anticancer isoreactivity, and the metal complexes such as its copper zinc has special catalytic property, significant aspect the simulation of metalloenzyme.Synthetic and the applied research of benzoglyoxaline and derivative thereof in decades is never interrupted, still very active so far.
Report about the synthesis technique of benzoglyoxaline is also a lot.The most promising method at present, the one, O-Phenylene Diamine and carboxylic acid (and derivative) for raw material synthetic, the 2nd, O-Phenylene Diamine and aldehydes react to prepare benzimidazoles compound.
The method that O-Phenylene Diamine and aldehydes are prepared benzimidazoles compound comprises two steps: be first that O-Phenylene Diamine and the condensation of aldehyde carbonyl form Schiff's base, then Schiff's base generation ring closure reaction, obtains benzimidazoles compound after oxydehydrogenation.Although can obtain benzimidazoles compound under strong oxidizer and heat-flash strong acidic condition, the method, due to the participation of oxygenant, makes by product more, and separation and purified product difficulty are large, and the by product of reaction is large to the pollution of environment.
The most frequently used method is the technique of O-Phenylene Diamine and carboxylic acid at present.The method is in strong acidic environment, conventionally hydrochloric acid, polyphosphoric acid or mixed acid system etc. are used as to catalyzer, under higher reaction temperatures, strongly-acid carboxylic acid or derivatives thereof and O-Phenylene Diamine carry out cyclisation and dehydration reaction, obtain having the heterogeneous ring compound of two N atoms.The method is widely used industrial, and product yield is high, quality good.
Summary of the invention
Main task of the present invention is to provide a kind of novel method of being prepared benzimidazoles compound by N-methyl-p-nitroaniline, is a kind of innovation in traditional synthesis and the method that obtains.Traditional technology is N-methyl-p-nitroaniline Br
2bromination reduction obtain 4-bromine O-Phenylene Diamine, and obtain 5-bromine benzoglyoxaline with carboxylic acid condensation reaction.The bottleneck of the method maximum be bromination and reduction process by product many, environmental pollution is large, and easily debrominate in reduction process, target productive rate is low, cost is high.
For solving the problems of the technologies described above, invented a kind of method of being prepared benzimidazoles compound by N-methyl-p-nitroaniline, it is characterized in that: take o-Nitraniline as raw material, adopt NBS bromo method to prepare bromo-2 N-methyl-p-nitroanilines of 4-, bromo-2 N-methyl-p-nitroanilines of 4-are through adopting a kind of special reductive agent sodium sulfite to be reduced to 4-bromine O-Phenylene Diamine, and 4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain target product 5-bromine benzoglyoxaline.
Further, o-Nitraniline adopts NBS bromo method to obtain bromo-2 N-methyl-p-nitroanilines of 4-, it is characterized in that: in described substitution reaction, o-Nitraniline is raw material, and acetic acid is as solvent, and NBS provides bromide anion, the lower sustained reaction 1h of boiling, obtains bromo-2 N-methyl-p-nitroanilines of yellow crystal crystallization 4-after separation.
Further, o-Nitraniline adopts NBS bromo method to obtain bromo-2 N-methyl-p-nitroanilines of 4-, it is characterized in that: in described substitution reaction, the mass ratio of o-Nitraniline and NBS, between 1:2 ~ 1:3, is slowly heated to boiling, sustained reaction 1h.
Further, bromo-2 N-methyl-p-nitroanilines of 4-, through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, is characterized in that: the bromo-2-N-methyl-p-nitroaniline of 4-is raw material, and ethanol is solvent, and sodium sulfite is reductive agent, and this reductive agent is Na
xs, K
2s
2o
3deng.Ethyl acetate is extracted, dried overnight, and concentrating under reduced pressure, obtains 4-bromine O-Phenylene Diamine solid.
Further, bromo-2 N-methyl-p-nitroanilines of 4-, through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, is characterized in that: reductive agent is Na
xs, K
2s
2o
3deng.
Further, bromo-2 N-methyl-p-nitroanilines of 4-are through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, it is characterized in that: the mass ratio of the bromo-2-N-methyl-p-nitroaniline of 4-and sodium sulfite is 1:9 ~ 1:11, and every 10h adds the V-Brite B of 2 times of bromo-2 N-methyl-p-nitroaniline quality of 4-.
Further, 4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain 5-bromine benzoglyoxaline, it is characterized in that: 4-bromine O-Phenylene Diamine be raw material, formic acid as dehydroamino acid, hydrochloric acid is catalyzer, Hybrid Heating backflow 4h obtains beige product 5-bromine benzoglyoxaline.
Further, 4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain 5-bromine benzoglyoxaline, it is characterized in that: 4-bromine O-Phenylene Diamine and formic acid mass ratio are 3:1 ~ 4:1, hydrochloric acid 5 mol/L, Hybrid Heating backflow 4h.
Reaction equation of the present invention is:
Advantage of the present invention is as follows: on the basis of traditional benzoglyoxaline synthesis technique, developed the bromo-2-N-methyl-p-nitroaniline reduction of a kind of 4-novel method, the reductibility of the method is moderate, and by product is few, and has overcome the shortcoming of easily de-Br-in traditional technology.With respect to traditional iron powder or sodium sulphite method of reducing, the method have pollute little, yield is high, product purity advantages of higher.With respect to metal catalyst method of reducing, the method has that cost is low, yield is high, quality is high, easily realize the advantages such as industrialization.Therefore, the method has extraordinary application prospect.
Specific embodiments
Example 1
Upper bromine stirs and adds 60g NBS to being dissolved with in the 500ml acetum of 23g 2-N-methyl-p-nitroaniline, is slowly heated to boiling, sustained reaction 1h, mixing solutions is poured in the water of 2L, then stirred 25min, suction filtration, it is 6～8 that filter cake is washed till to pH value with distilled water, dry, obtains the bromo-2-N-methyl-p-nitroaniline of 4-crude product, by solid crude product acetonitrile recrystallization, cooling placement, obtains yellow crystal, suction filtration, be dried to obtain fine work 35g(96.3%), HPLC content 98.4%, mp 110-114 ℃.
Example 2
Nitroreduction adds the bromo-2-N-methyl-p-nitroaniline of 4-10.8g(50mmol in the there-necked flask of 500ml), ethanol 300ml, dropwise adds distilled water 40ml under agitation condition, every 10h adds V-Brite B 22.0g, stirring heating backflow 48h, and TLC tracks to and reacts completely, separate water layer, with ethyl acetate extraction three times, each 100ml, united extraction liquid, dried overnight, concentrating under reduced pressure, obtains 4-bromine O-Phenylene Diamine solid 6.8g(72.7%), HPLC content 95.7%, 64 ~ 70 ° of C of mp.
Example 3
4-bromine O-Phenylene Diamine 5.1g(9mmol is got in cyclization), formic acid 1.5g, 5mol/L hydrochloric acid 15ml, Hybrid Heating backflow 4h, is coolingly adjusted to PH=6 ~ 7 with ammoniacal liquor afterwards, suction filtration, obtains yellow powder 5-bromine benzoglyoxaline 4.2g(78.1%), use 30ml V
ethanol: V
waterthe crystallization of=1:1 solution weight, obtains beige crystalline solid, HPLC content 98.4%, mp 130-134 ℃.
Claims (8)
1. a method prepared by the bromo-benzoglyoxaline of 5-, it is characterized in that: take o-Nitraniline as raw material, adopt NBS bromo method to prepare bromo-2 N-methyl-p-nitroanilines of 4-, bromo-2 N-methyl-p-nitroanilines of 4-are through adopting a kind of special reductive agent sodium sulfite to be reduced to 4-bromine O-Phenylene Diamine, and 4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain target product 5-bromine benzoglyoxaline.
2. according to claim 1, o-Nitraniline adopts NBS bromo method to obtain bromo-2 N-methyl-p-nitroanilines of 4-, it is characterized in that: in described substitution reaction, o-Nitraniline is raw material, acetic acid is as solvent, NBS provides bromide anion, and the lower sustained reaction 1h of boiling, obtains bromo-2 N-methyl-p-nitroanilines of yellow crystal 4-after separation.
3. according to claim 2, o-Nitraniline adopts NBS bromo method to obtain bromo-2 N-methyl-p-nitroanilines of 4-, it is characterized in that: in described substitution reaction, the mass ratio of o-Nitraniline and NBS, between 1:2 ~ 1:3, is slowly heated to boiling, sustained reaction 1h.
According to claim Isosorbide-5-Nitrae-bromo-2 N-methyl-p-nitroanilines through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, it is characterized in that: the bromo-2-N-methyl-p-nitroaniline of 4-is raw material, ethanol is solvent, sodium sulfite is reductive agent, and this reductive agent is NaxS, K2S2O3 etc.; Ethyl acetate is extracted, dried overnight, and concentrating under reduced pressure, obtains 4-bromine O-Phenylene Diamine solid.
5. according to claim 4, bromo-2 N-methyl-p-nitroanilines of 4-, through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, is characterized in that: reductive agent is NaxS, K2S2O3 etc.
6. according to claim 4, bromo-2 N-methyl-p-nitroanilines of 4-are through adopting a kind of special reductive agent to be reduced to 4-bromine O-Phenylene Diamine, it is characterized in that: the mass ratio of the bromo-2-N-methyl-p-nitroaniline of 4-and sodium sulfite is 1:9 ~ 1:11, and every 10h adds the V-Brite B of 2 times of bromo-2 N-methyl-p-nitroaniline quality of 4-.
7. according to claim 1,4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain 5-bromine benzoglyoxaline, it is characterized in that: 4-bromine O-Phenylene Diamine be raw material, formic acid as dehydroamino acid, hydrochloric acid is catalyzer, Hybrid Heating backflow 4h, obtains beige product 5-bromine benzoglyoxaline.
8. according to claim 7,4-bromine O-Phenylene Diamine and formic acid condensation reaction obtain 5-bromine benzoglyoxaline, it is characterized in that: 4-bromine O-Phenylene Diamine and formic acid mass ratio are 3:1 ~ 4:1, hydrochloric acid 5 mol/L, Hybrid Heating backflow 4h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018212162A1 (en) * | 2017-05-17 | 2018-11-22 | 株式会社トクヤマ | Method for producing diaminobenzene compound |
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| WO2013026914A1 (en) * | 2011-08-25 | 2013-02-28 | F. Hoffmann-La Roche Ag | Serine/threonine pak1 inhibitors |
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2013
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Patent Citations (5)
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| WO2000040554A1 (en) * | 1999-01-07 | 2000-07-13 | American Home Products Corporation | Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression |
| WO2002055077A1 (en) * | 2001-01-11 | 2002-07-18 | Smithkline Beecham Corporation | Use of imidazolyl cyclic acetal derivatives in the manufacture of a medicament for the treatment of diseases mediated by the alk5 receptors |
| WO2008021851A2 (en) * | 2006-08-09 | 2008-02-21 | Smithkline Beecham Corporation | Novel compounds as antagonists or inverse agonists for opioid receptors |
| WO2013026914A1 (en) * | 2011-08-25 | 2013-02-28 | F. Hoffmann-La Roche Ag | Serine/threonine pak1 inhibitors |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018212162A1 (en) * | 2017-05-17 | 2018-11-22 | 株式会社トクヤマ | Method for producing diaminobenzene compound |
| CN110621652A (en) * | 2017-05-17 | 2019-12-27 | 株式会社德山 | Process for producing diaminobenzene compound |
| JPWO2018212162A1 (en) * | 2017-05-17 | 2020-03-19 | 株式会社トクヤマ | Method for producing diaminobenzene compound |
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Application publication date: 20140416 |