CN108727276A - The preparation method of benzimidizole derivatives - Google Patents
The preparation method of benzimidizole derivatives Download PDFInfo
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- CN108727276A CN108727276A CN201810659223.7A CN201810659223A CN108727276A CN 108727276 A CN108727276 A CN 108727276A CN 201810659223 A CN201810659223 A CN 201810659223A CN 108727276 A CN108727276 A CN 108727276A
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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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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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
- C07D487/02—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 two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of preparation method of benzimidizole derivatives, the benzimidizole derivatives are the bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5-, are the intermediates for preparing anticancer drug and organic electro luminescence device.Raw materials and reagents used in the method for the synthesis bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5- of the present invention are cheap and easy to get, synthetic method simple possible, reaction condition is mild, and yield is higher, and an easy synthesis path is opened up for the synthesis bromo- 1H- benzimidazole compounds of 1- methyl -2- phenyl -5-.
Description
The application is application No. is 201510928744.4, and the applying date is on December 15th, 2015, and invention and created name is
The divisional application of the application for a patent for invention of " benzimidizole derivatives and preparation method thereof ".
Technical field
The present invention relates to a kind of preparation methods of benzimidizole derivatives.
Background technology
Benzimidizole derivatives are a kind of compounds with extensive bioactivity, are had in field of medicaments antiviral, anti-
Cancer, anti parasitic, antiatherosclerosis, anti-inflammatory, antihistamine, treatment leukaemia, treatment peptic ulcer, treatment hypoglycemia and
Physiologic derangement, blood pressure lowering and other effects.Nitrobenzimidazole class has preferable radiation sensitizing effect in radiotherapy.Benzo miaow
Zole derivatives can be used for simulating the active site research bioactivity of natural superoxide dismutase, and it is novel to can be used as epoxy resin
Curing agent, catalyst and certain metallic surface inorganic agents, are alternatively arranged as the intermediate etc. of organic synthesis.
Since acid has corrosion to all kinds of metal equipments, so corrosion inhibiter to be added in pickling, inhibit metal in acidity
Corrosion in medium.Benzimidazoles compound toxicity is low, therefore this kind of compound has as restrainer and greatly opens
It makes an offer value, there is good corrosion resistance.Benzimidazole due to 1,3 upper two nitrogen-atoms high activity and easily in metal watch
Adsorbed on face, especially its derivative due to different substituents and in metal surface with different adsorption capacities, so as to
Corrosion inhibition is improved by selecting suitable substituent group（Quoted from bibliography）.
Benzimidazoles compound can inhibit fungus grown, probenazole（thiabendazole）, benomyl
（benomyl）, carbendazim（carbendazim）It is the commodity fungicide of three kinds of representativeness active groups containing benzimidazole, mainly
For preventing crops, on industrial crops by fungus-caused various diseases.
In addition, benzimidazoles compound can prepare complex for Organic Light Emitting Diode material with rare earth element coordination
Equal fields.Polybenzimidazoles class compound is to be used for one of the heterocyclic polymer of high temperature resistant binder earliest, there is moment high temperature resistant
Low temperature resistant alternation and ultralow temperature performance, polybenzimidazole resin can be used as heat-resisting material to be used for space industry.
Invention content
Technical problem to be solved by the invention is to provide a kind of preparation methods of benzimidizole derivatives.
A kind of benzimidizole derivatives, the benzimidizole derivatives are the bromo- 1H- benzos miaows of 1- methyl -2- phenyl -5-
Azoles, structural formula are as follows：。
Realize that the technical solution of the object of the invention is the preparation side of the bromo- 1H- benzimidazoles of above-mentioned 1- methyl -2- phenyl -5-
Method includes the following steps：
1. preparing N- methyl -2- nitro -4- bromanilines by N- methyl -2- nitroanilines and anhydrous bromine.
2. 1. N- methyl -2- nitro -4- bromanilines that step is prepared, which are carried out N- benzoylations, is obtained by the reaction N- (- 2- nitre
Base -4- bromophenyls)-N-methyl-benzamide.
3. being restored to the nitro of step 2. N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide obtained, N- is made
(- 2- amino -4- bromophenyls)-N-methyl-benzamide.
4. 3. N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide that step is prepared is carried out intramolecular dehydration to close
The bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5- are made in ring reaction.
1. the molar ratio of middle N- methyl -2- nitroanilines and anhydrous bromine is 1.0 to step:1.1~1.2, it will meet above-mentioned
N- methyl -2- the nitroanilines of ratio requirement are dissolved in anhydrous acetic acid, the aqueous acetic acid solution reaction of anhydrous bromine are added dropwise, instead
It is 20~40 DEG C to answer temperature, and the reaction time is 3~6 h.The a large amount of orange solids of later stage appearance are reacted, filters obtain after reaction
Solid with aqueous sodium carbonate wash remove solid present in hydrogen bromide and a small amount of bromine, be washed with water and wash neutrality.It examines
Considering bromine has a small amount of volatilization, so the molar ratio of N- methyl -2- nitroanilines and anhydrous bromine is 1.0:1.1~1.2, both may be used
So that the reaction of N- methyl -2- nitroanilines is more complete, and prevent the generation of two bromination products.
Step 1. in N- methyl -2- nitroanilines when being dissolved in anhydrous acetic acid, the quality of solvent anhydrous acetic acid is N- first
4.0~6.0 times of base -2- nitroaniline quality；Anhydrous bromine and anhydrous acetic acid in the aqueous acetic acid solution of the anhydrous bromine
Mass ratio be 1.8~2.0:1.
2. the ratio between the amount of substance of middle N- methyl -2- nitro -4- bromanilines and chlorobenzoyl chloride is 1.0 to step:1.1~1.3；
Temperature is 85~95 DEG C when reaction, and the reaction time is 6~8 h.
Step 2. in by N- methyl -2- nitro -4- bromanilines be dissolved in pyridine after and chlorobenzoyl chloride under protection of argon gas
Reaction；The quality of pyridine is 2.5~3.5 times of N- methyl -2- nitro -4- bromaniline quality.Pyridine in reaction system is both
Acid binding agent, and be solvent.After the completion of reaction, ethyl acetate is added, a large amount of pyridine hydrochloride precipitations are precipitated, removed by filtering, second
Also contain a large amount of pyridines in acetoacetic ester filtrate, suitable dilute hydrochloric acid is added, remaining pyridine is dissolved in water at salt, product
It is dissolved in ethyl acetate, water layer and organic layer separation, to remove the pyridine in product.
According to the literature（WO20110869 41A1, WO2011086935A1, US 20120153268）, crude product use
Silica gel column chromatography detaches, eluant, eluent：Dichloromethane, experiment discovery are undesirable with dichloromethane eluant separating effect.Trial is adopted
Use petrol ether/ethyl acetate（3:1）Make solvent, product and raw material separation are preferable.Crude product adds petrol ether/ethyl acetate（3:
1）Dissolving, as a result has been surprisingly found that raw material is soluble, and product slightly soluble, adds appropriate petrol ether/ethyl acetate（3:1）Make unreacted
Dissolution of raw material, most of solid product is still insoluble.Solution and solid are detached with decantation, solid use again petroleum ether/
Ethyl acetate（3:1）Washing just obtains a large amount of pure products, and solution carries out column chromatography, eluant, eluent：Petrol ether/ethyl acetate
（3:1）, portion of product of getting back.With document report（WO2011086941 A1, WO2011086935A1, US20120153268）
Silica gel column chromatography separation method compare, can realize separation with a small amount of silica gel and eluant, eluent.
Step 3. in N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamides and reducing agent are mixed, it is molten mixing
Agent：The reduction reaction that nitro occurs in THF/ water/methanol, obtains N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide；
The ratio between amount of substance of N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamides and reducing agent is 1.0:4.5~5.5.As
Preferably, the reducing agent is sodium dithionite.The quality of THF is N- (- 2- nitro -4- bromophenyls)-N- toluyls
8~12 times of amine quality, the quality of water are 8~11 times of N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide quality.
Step 3. in N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide when being reacted with reducing agent, reaction temperature is
20~35 DEG C, the reaction time is 2~4 h.
Step 4. in using dimethylbenzene as solvent, N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide is to toluene sulphur
Under acid catalysis, ring-closure reaction occurs, obtains the bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5-.
Step 4. in dimethylbenzene quality be N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide quality 3~4
Times, the quality of catalyst p-methyl benzenesulfonic acid be N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide quality 0.15~
0.25 times.Ring-closure reaction temperature is that under reflux conditions, the reaction time is 5~9 h.
The present invention has the effect of positive：（1）The bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5- prepared by the present invention can
As the intermediate for synthesizing following three compounds 1~3.Compound 1~3 is mammal rapamycin target protein
（mammalian target of rapamycin）The inhibitor of kinases is expected to the drug as treating cancer.When 1- methyl-
After bromine atom in the bromo- 1H- benzimidazoles of 2- phenyl -5- is replaced by polycyclic aromatic hydrocarbon, the compound of formation belongs to organic electric-field
Electroluminescence device.
（2）Raw materials and reagents used in the present invention are cheap and easy to get, and synthetic method simple possible, reaction condition is mild, yield compared with
Height opens up an easy synthesis path for the synthesis bromo- 1H- benzimidazole compounds of 1- methyl -2- phenyl -5-.
Specific implementation mode
（Embodiment 1）
The benzimidizole derivatives of the present embodiment are bromo- 1H- benzos [d] imidazoles of 1- methyl -2- phenyl -5-, and structural formula is as follows：
Preparation method includes the following steps：
1. preparing N- methyl -2- nitro -4- bromanilines, reaction equation is as follows
。
In being mounted with 1000 mL three-necked bottles of electric mixer and constant pressure funnel, 60 g are added（394 mmol）N- first
Base -2- nitroanilines, then 230 mL anhydrous acetic acids, which are added, into three-necked bottle makes N- methyl -2- nitroanilines dissolve；The constant pressure
Added with 35 mL anhydrous acetic acids and 69.7 g in funnel（436 mmol）Anhydrous bromine.
The acetic acid solution that bromine is added dropwise in lower opening constant pressure funnel, exothermic heat of reaction, in room temperature 25 after being added dropwise is stirred at room temperature
4 h are reacted at DEG C, the reaction was complete for thin-layer chromatography detection（Solvent：Dichloromethane）, after the reaction the phase there are a large amount of orange solids.
Material in three-necked bottle is filtered after reaction, filtrate adds suitable quantity of water not have solid precipitation, the solid filtered
It first washed once with the aqueous sodium carbonate of 260 mL5%, then be washed with deionized 2 times, every time 330 mL；What washing was completed
Standard is that the washings pH value of last time is 7.0.
By the solid vacuum drying after washing, 80.33 g orange/yellow solid products, yield 88% are obtained.Detect product
M.p.101.9~102.7 DEG C, the m.p. literature values of N- methyl -2- nitro -4- bromanilines：101.9-102.4 ℃（J Org
Chem, 1970, 35(4):965-969）.
Product nuclear magnetic resonance characterizes：1H-NMR（400MHz, CDCl3, δ ppm）:8.32 (s, 1H, ArH), 8.02
(s, b, 1H, NH), 7.52 (d, J=8Hz, 1H, ArH), 6.76 (d, J=8Hz, 1H, ArH), 3.03
(s, 3H, CH3).IR (KBr), ν/cm-1:3380~3150 (b ,-NH), 1560,1344 (- NO2), 1616,
1507 (phenyl ring skeletons), 875,809 (phenyl ring 1,2, the substitutions of 4- ternarys), 691 (C-Br).
When the anhydrous acetic acid that the present embodiment uses prepares, it is to take commercially available anhydrous acetic acid, phosphorus pentoxide is added thereto,
It is heated to reflux, then distillation obtains the anhydrous acetic acid that the present embodiment uses.
When the anhydrous bromine that the present embodiment uses prepares, it is that concentrated sulfuric acid shaking water removal is added into bromine, then separates
To the anhydrous bromine used.
2. preparing N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide, reaction equation is as follows.
1. 68 g that step is prepared（290 mmol）N- methyl -2- nitro -4- bromanilines are dissolved in 200 mL pyridines, are added
Enter into 500 mL three-necked bottles, then 50 g of chlorobenzoyl chloride is added into three-necked bottle（350 mmol）, under protection of argon gas, magnetic force stirs
It mixes down and reacts 7 h after being heated to 90 DEG C, the reaction was complete for thin-layer chromatography detection（Solvent：Petrol ether/ethyl acetate（3:1））.
2000 mL of ethyl acetate is added into material after reaction, a large amount of pyridine hydrochloride solids occurs, filters,
Solid is washed with ethyl acetate.It filters obtained ethyl acetate filtrate to be washed with 800 mL10% hydrochloric acid solutions, separates organic phase,
Organic phase first washs secondary, 800 mL every time with 10% solution of potassium carbonate so that pH=8 of organic phase, then be saturated with 800 mL
Common salt aqueous solution washed once, and anhydrous magnesium sulfate is added after saturated common salt water washing and dries organic phase.
By the organic phase filtering after drying, obtained filtrate decompression distillation removal solvent, the residue obtained after distillation adds
Enter petrol ether/ethyl acetate（3:1）In the mixed solvent finds that unreacted raw material is soluble, and product not readily dissolves.With coming down in torrents
Method detaches solution and solid, and solution carries out column chromatography, eluant, eluent：Petrol ether/ethyl acetate（3:1）, 28 g of product is obtained, is inclined
The solid petrol ether/ethyl acetate that catharsis obtains（3:1）Washing, obtains 63 g of product, total to obtain the green white solids of 91 g,
Yield is 94%.
M.p.114.3-114.7 DEG C of product.
Product nuclear magnetic resonance characterizes：1H-NMR（400MHz, DMSO-d6, δ ppm）:7.89~7.85 (m, 3H, ArH),
7.65~7.57 (m, 4H, ArH), 7.46~7.44 (m, 1H, ArH), 3.89 (s, 3H, CH3).IR (KBr), ν/
cm-1: 2937( -CH3), 1654 (C=O), 1530,1348 (- NO2), 1598,1577,1475 (phenyl ring skeletons),
699 (C-Br)。
3. preparing N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide, reaction equation is as follows
。
2. 19 g that step is prepared（56 mmol）N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide is dissolved in
In 200 mL THF, it is then added in 1000 mL three-necked bottles, Na is added under room temperature magnetic agitation under protection of argon gas2S2O4
3 h of reaction are stirred at room temperature in 20 mL of aqueous solution and methanol；Na used2S2O4Aqueous solution is by 50 g（284 mmol）With 180 mL of water
Composition.
Ethyl acetate 200 mL and NaHCO is added into material after reaction3Aqueous solution stirs 1 h, institute at room temperature
State NaHCO3Aqueous solution is by 24 g NaHCO3It is formed with 250 mL water.
It is extracted with ethyl acetate, removes water layer, the Na of 140 mL 10% of organic layer2CO3Aqueous solution and 140 mL saturation foods
Brine respectively washed once, anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, obtains 15.6 g of white solid, yield 91%,
146.6~147.8 DEG C of product m.p.；Nuclear magnetic resonance characterizes：1H-NMR（400MHz, CD3CN, δ ppm）:7.88 (s, 1H,
Ar), 7.80~7.77 (m, 2H, ArH), 7.58~7.55 (m, 3H, ArH), 7.48~7.43 (m, 2H, ArH),
6.62 (s, b, 1H, NH), 6.09 (s, b, 1H, NH), 3.83 (s, 3H, CH3).IR (KBr), ν/cm-1:
3475,3329 (b ,-NH2), 1662 (C=O), 1600,1575,1469, (skeleton of phenyl ring), 705 (C-Br).
4. synthesizing the bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5-, reaction equation is as follows
。
3. 15.6 g that step is prepared are added in 200 mL three-necked bottles（52 mmol）N- (- 2- amino -4- bromophenyls)-N-
Methyl benzamide and 50 mL dimethylbenzene, gained suspension add 3.0 g of monohydrate of p-methyl benzenesulfonic acid again（15.4 mmol）,
It is heated to reflux 7 h.
Reflux terminates postcooling, filters, and will filter obtained solid and is dissolved in 180 mL dichloromethane, gained dichloromethane
Solution respectively washed once with 100 mL, 10% solution of potassium carbonate and 100 mL saturated salt solutions, dry with anhydrous magnesium sulfate after washing
Dry, decompression steams solvent.
Obtained filtrate will be filtered to be concentrated to dryness, obtained solid also is soluble in dichloromethane, filters to obtain with above-mentioned processing
The washing of solid same method and dried recovered organic matter.
Merge organic matter twice, silica gel column chromatography, eluant, eluent：Petrol ether/ethyl acetate（3:1）, obtain white crystals
13.0 g, yield 87%.
150.0~150.3 DEG C of product m.p..
Product nuclear magnetic resonance characterizes：1H-NMR（400MHz, DMSO-d6, δ ppm）:7.89~7.85 (m, 3H, Ar),
7.65~7.58 (m, 4H, Ar), 7.46~7.43 (m, 1H, Ar), 3.88 (s, 3H, CH3)；13C-NMR
（100MHz, DMSO-d6, δ ppm）:154.7,144.3,136.2,130.4,130.1,129.8,129.2,
125.5,121.8,114.7,113.0,32.4.IR (KBr), ν/cm-1:1608 (C=N), 699 (C-Br).HPLC:
99.8%。
（Application examples）
The bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5- prepared by the present invention can be used as following three compounds 1~3 of synthesis
Intermediate.Compound 1~3 is mammal rapamycin target protein（mammalian target of rapamycin）Swash
The inhibitor of enzyme is expected to the drug as treating cancer.Bromine atom in the bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5-
After being replaced by polycyclic aromatic hydrocarbon, the compound of formation belongs to organic electro luminescence device.
Claims (5)
1. a kind of preparation method of benzimidizole derivatives, the structural formula of the benzimidizole derivatives are as follows
It is characterized in that preparation method includes the following steps：
1. preparing N- methyl -2- nitro -4- bromanilines, N- methyl -2- nitre by N- methyl -2- nitroanilines and the reaction of anhydrous bromine
The molar ratio of base aniline and anhydrous bromine is 1.0:1.1~1.2；N- methyl -2- nitroanilines are dissolved in anhydrous acetic acid, so
The aqueous acetic acid solution that anhydrous bromine is added dropwise afterwards starts to react, and reaction temperature is 20~40 DEG C, and the reaction time is 3~6h；
When wherein N- methyl -2- nitroanilines are dissolved in anhydrous acetic acid, the quality of solvent anhydrous acetic acid is N- methyl -2- nitros
4.0~6.0 times of aniline quality, the mass ratio of anhydrous bromine and anhydrous acetic acid is 1.8 in the aqueous acetic acid solution of anhydrous bromine
~2.0:1；
2. 1. N- methyl -2- nitro -4- bromanilines that step is prepared are carried out N- benzoylations with chlorobenzoyl chloride is obtained by the reaction N-
(- 2- nitro -4- bromophenyls)-N-methyl-benzamide；The amount of the substance of N- methyl -2- nitro -4- bromanilines and chlorobenzoyl chloride
The ratio between be 1.0:1.1~1.3；Temperature is 85~95 DEG C when reaction, and the reaction time is 6~8 h；
3. being restored to the nitro of step 2. N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamide obtained, N- (- 2- are made
Amino -4- bromophenyls)-N-methyl-benzamide；Wherein by N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamides and also
Former agent mixing, in mixed solvent：The reduction reaction that nitro occurs in THF/ water/methanol, obtains N- (- 2- amino -4- bromophenyls) -
N-methyl-benzamide；The ratio between the amount of substance of N- (- 2- nitro -4- bromophenyls)-N-methyl-benzamides and reducing agent is
1.0:4.5~5.5；The reducing agent is sodium dithionite；
4. it is anti-that 3. N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide that step is prepared carries out intramolecular dehydration closed loop
The bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5- should be made.
2. the preparation method of benzimidizole derivatives according to claim 1, it is characterised in that：Step 2. in by N- first
Base -2- nitro -4- bromanilines react after being dissolved in pyridine with chlorobenzoyl chloride under protection of argon gas；The quality of pyridine is N- first
2.5~3.5 times of base -2- nitro -4- bromaniline quality.
3. the preparation method of benzimidizole derivatives according to claim 1, it is characterised in that：Step 3. in N- (- 2- nitre
Base -4- bromophenyls) for-N-methyl-benzamide when being reacted with reducing agent, reaction temperature is 20~35 DEG C, the reaction time is 2~4
h。
4. the preparation method of benzimidizole derivatives according to claim 1, it is characterised in that：Step 4. in dimethylbenzene
For solvent, N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide occurs ring-closure reaction, obtains under Catalyzed by p-Toluenesulfonic Acid
To the bromo- 1H- benzimidazoles of 1- methyl -2- phenyl -5-.
5. the preparation method of benzimidizole derivatives according to claim 4, it is characterised in that：Step 4. in dimethylbenzene
Quality is 3~4 times of N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide quality, the quality of catalyst p-methyl benzenesulfonic acid
It is 0.15~0.25 times of N- (- 2- amino -4- bromophenyls)-N-methyl-benzamide quality；Ring-closure reaction is anti-under reflux
Answer 5~9 h.
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| CN102471269A (en) * | 2010-01-15 | 2012-05-23 | 出光兴产株式会社 | Nitrogen-containing heterocyclic derivative and organic electroluminescent element containing same |
| WO2014182929A1 (en) * | 2013-05-09 | 2014-11-13 | Gilead Sciences, Inc. | Benzimidazole derivatives as bromodomain inhibitors |
| WO2015128333A1 (en) * | 2014-02-27 | 2015-09-03 | Laboratoire Biodim | Heteroaromatic derivatives and their use as pharmaceuticals |
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Application publication date: 20181102 |