CN101759686A - Synthesizing method and application of 2-substituted aryl-1-substituted benzyl benzimidazole compound - Google Patents
Synthesizing method and application of 2-substituted aryl-1-substituted benzyl benzimidazole compound Download PDFInfo
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Abstract
The invention discloses a synthesizing method of a 2-substituted aryl-1-substituted benzyl benzimidazole compound, comprising the following steps of: adding an o-phenylenediamine compound to a reactor; adding a water-alcohol mixed solvent with 30-100 times by weight of the o-phenylenediamine compound under the stirring; then adding aromatic aldehyde, wherein the mole ratio of the o-phenylenediamine compound to the aromatic aldehyde is 1 to 2.0-2.5; then heating, refluxing and then adding a weed acid catalyst after relfuxing; continuously relfuxing and reacting for 30-90 minutes, finishing reaction; and then pouring a reaction mixture into ice water to sequentially perform stirring, pumping filtration, washing and alcohol recrystallization so as to obtain the 2-substituted aryl-1-substituted benzyl benzimidazole compound. The synthesizing method has short synthetic route, high yield coefficient, simple and moderate reaction condition, easy operation, high atom utility ratio, easy recycling of a reaction solvent in a water-alcohol system, low cost and easy obtaining of the catalyst; the whole reaction process reflects a green synthetic chemistry idea; and in addition, the obtained 2-substituted aryl-1-substituted benzyl benzimidazole compound has higher inhibitor for a thioformamide peptidase.
Description
Technical field
The invention belongs to benzo-aza cyclic cpds technical field, be specifically related to benzimidazole compound and derivative thereof.
Background technology
Benzimidazoles compound has biological activity preferably, and many benzimidazoles derivatives have all demonstrated excellent antibiotic, hypertension, antitumour activity in clinical treatment.Benzimidazoles derivative also can be used for simulating the reactive site of natural superoxide-dismutase and studies biological activity with this.In benzimidazoles compound, have been found that at present some compounds have good pharmacologically active, for example can be used as omeprazole, lansoprazole of proton pump inhibitor etc.
The benzimidazoles compound that contains different substituents should have different biological activitys, by the bioactivity screening to this compounds, in the hope of finding antibiotic, the antiviral class medicine or the proton pump inhibitor of better high-efficiency low-toxicity.So the synthetic and applied research of this compounds enjoys medical chemistry men's concern always.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of 2-substituted aryl-1-substituted benzyl benzimidazole compound, and this compounds is as the application of the inhibitor of first sulphamide peptase.
For achieving the above object, the technique means that the present invention taked is: the synthetic method of this 2-substituted aryl-1-substituted benzyl benzimidazole compound is:
Add the O-Phenylene Diamine compound in reactor, adding weight under stirring is O-Phenylene Diamine compound 30-100 water alcohol mixed solvent doubly, adds aromatic aldehyde again, and the mol ratio of described O-Phenylene Diamine compound and aromatic aldehyde is 1: 2.0-2.5; Then heating, the back of waiting to reflux adds weak acid class catalyzer; Continue back flow reaction 30～90min, finish reaction; Carry out TLC then and follow the tracks of reaction process, reaction mixture is poured in the frozen water stir successively, suction filtration, washing, ethyl alcohol recrystallization, obtain 2-substituted aryl-1-substituted benzyl benzimidazole compound.
Further, weak acid class catalyzer of the present invention is an oxalic acid, perhaps is oxalate and sour mixture.
Further, water alcohol mixed solvent of the present invention is the mixing solutions of second alcohol and water.
The 2-substituted aryl that the above synthetic method of the present invention obtains-1-substituted benzyl benzimidazole compound has suc as formula the general structure shown in (I)
Wherein, R, R
1, R
2Group is-NO
2,-N (CH
3)
2,-OH ,-OCH
3, H, 3,4-OCH
2O-,-Br ,-Cl, F ,-in the alkyl of COOH, 1-6 carbon, the cycloalkyl of 3-7 carbon any.R, R
1, R
2The three can be identical, also can be inequality.
The purposes of 2-substituted aryl of the present invention-1-substituted benzyl benzimidazole compound is: this compound is as the inhibitor of first sulphamide peptase.
The present invention has measured the inhibiting rate of this compounds to yeast methionine(Met) peptase (ScMetAP1).The methionine(Met) peptase is the proteolytic enzyme that extensively is present in a kind of necessity in prokaryotic organism (as colibacillus) and the eukaryote living things systems such as (as yeast, Mammalss), its physiological function mainly is the shearing that participates in new synthetic proteins N end methionine(Met), and there is important effect correct location and physiological degraded in vivo biological activity of albumen, the cell for keeping.The result shows that 2-substituted aryl of the present invention-1-substituted benzyl benzimidazole compound has high inhibitory to methionine(Met) peptase (ScMetAP1).
The present invention is that the method for raw material Synthetic 2-substituted aryl-1-substituted benzyl benzimidazole compound has the following advantages with the O-Phenylene Diamine:
(1) synthetic route is short, and the productive rate height;
(2) reaction conditions is simply gentle, easy handling;
(3) atom utilization height; Reaction solvent is a water alcohol system, is easy to recycle; Used catalyzer cheap and easy to get, whole process has embodied the theory of green synthetic chemistry.
Embodiment
1, synthetic embodiment
Agents useful for same of the present invention and instrument are: X-4 type micro melting point apparatus (temperature is not proofreaied and correct); Avatar370 FT-TR (Nicolet infrared spectrometer (KBr compressing tablet); Bruker 400 UltraShield
TM(400MHz) nuclear magnetic resonance analyser; Deuterium is a solvent for DMSO, and TMS is interior mark.Agents useful for same is commercially available analytical pure.
Embodiment one:
In reactor, add successively O-Phenylene Diamine (2mmol, 0.21g), ethanol water mixed solvent (6mL, about 6g), stirring and dissolving.In this solution, add phenyl aldehyde (4mmol).Heat temperature raising, the back of waiting to reflux adds oxalic acid (0.2mmol), continues to be back to reaction and finishes, and reaction mixture is poured in the frozen water of 80mL, stirs 30min, suction filtration, washing, ethyl alcohol recrystallization.Get 2-phenyl-1-benzyl benzimidazole.White solid; Productive rate 86%; M.p.131-132 ℃; IR (KBr): 3060 (v=C-H), 2926 (v-C-H), 1489 (v-C=N), 726,699 (δ=C-H), 1598 (phenyl ring skeletons);
1H-NMR (DMSO): δ: 5.57 (s, 2H), 10:R=4-OH6.98 (d, 2H), 7.21-7.28 (m, 5H), 7.50-7.53 (m, 4H), 7.69-7.74 (m, 3H).
Embodiment two:
In reactor, add successively O-Phenylene Diamine (2mmol, 0.21g), ethanol water mixed solvent (10mL, about 10g), stirring and dissolving.In this solution, add p-Hydroxybenzaldehyde (4.5mmol).Heat temperature raising, (0.1M 2mL), continues to be back to reaction and finishes, and reaction mixture is poured in the frozen water of 80mL, stirs 30min, suction filtration, washing, ethyl alcohol recrystallization for wait to reflux back adding sodium oxalate (0.2mmol) and HCl.Get 2-(4-hydroxyl) phenyl-1-(4-hydroxyl) benzyl benzimidazole.White powder; Productive rate 76%; M.p.223-224 ℃; IR (KBr): 3259 (v-O-H), 3024 (v=C-H), 2803 (v-C-H), 1443 (v-C=N), 839,815 (δ=C-H), 1611 (phenyl ring skeletons).
1H-NMR (DMSO): δ: 5.41 (s, 2H), 9.39 (s, 1H), 9.95 (s, 1H), 6.64-6.66 (d, 2H), and 6.81-6.83 (d, 2H), 6.88-6.90 (d, 2H), 7.18-7.22 (m, 2H), 7.40-7.42 (d, 1H), 7.54-7.56 (d, 2H), 7.64-7.65 (d, 1H).
Embodiment three:
In reactor, add successively O-Phenylene Diamine (2mmol, 0.21g), ethanol water mixed solvent (8mL, about 8g), stirring and dissolving.In this solution, add 2-hydroxy benzaldehyde (4.1mmol).Heat temperature raising, the back of waiting to reflux adds sodium oxalate (0.25mmol) and H
2SO
4(0.05M 2mL), continues to be back to reaction and finishes, and reaction mixture is poured in the frozen water of 80mL, stirs 30min, suction filtration, washing, ethyl alcohol recrystallization.Get 2-(2-hydroxyl) phenyl-1-(2-hydroxyl) benzyl benzimidazole.Pale yellow powder; Productive rate 84%; M.p.209-210 ℃; IR (KBr): 3296 (v-O-H), 3049 (v=C-H), 2947 (v-C-H), 1452 (v-C=N), 753 (δ=C-H), 1593 (phenyl ring skeletons).
1H-NMR (DMSO): δ: 5.39 (s, 2H), 6.38-6.39 (d, 1H), 6.57-6.61 (t, 1H), 6.81-6.83 (d, 1H), 6.88-6.92 (t, 1H), 7.03-7.04 (d, 2H), and 7.19-7.27 (m, 2H), 7.34-7.43 (m, 3H), 7.70-7.72 (d, 1H), 10.86 (2H, brs).
Embodiment four:
In reactor, add successively O-Phenylene Diamine (2mmol, 0.21g), ethanol water mixed solvent (15mL, about 15g),, stirring and dissolving.In this solution, add 4-methoxybenzaldehyde (4mmol).Heat temperature raising, the back of waiting to reflux adds sodium oxalate (0.2mmol) and tosic acid (0.2mmol), continues to be back to reaction and finishes, and reaction mixture is poured in the frozen water of 80mL, stirs 60min, suction filtration, washing, ethyl alcohol recrystallization.Get 2-(4-methoxyl group) phenyl-1-(4-methoxyl group) benzyl benzimidazole.White powder; Productive rate 77%; M.p.127-128 ℃; IR (KBr): 3055 (v=C-H), 2912 (v-C-H), 1512 (v-C=N), 829 (δ=C-H), 1611 (phenyl ring skeletons).
1H-NMR (DMSO) δ: 6.84-7.85 (m, 12H), 5.39 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H).
Embodiment five:
In reactor, add successively O-Phenylene Diamine (2mmol, 0.21g), ethanol water mixed solvent (20mL, about 20g), stirring and dissolving.In this solution, add 3,4-acetal radical phenyl aldehyde (5mmol).Heat temperature raising, the back of waiting to reflux adds oxalic acid (0.2mmol), continues to be back to reaction and finishes, and reaction mixture is poured in the frozen water of 80mL, stirs 90min, suction filtration, washing, ethyl alcohol recrystallization.Get 2-(3, the 4-acetal radical) phenyl-1-(3, the 4-acetal radical) benzyl benzimidazole.White powder; Productive rate 81%; M.p.171-173 ℃; IR (KBr): 3019 (v=C-H), 2900 (v-C-H), 1483 (v-C=N), 816,740 (δ=C-H), 1607 (phenyl ring skeletons), 1249 (v-C-O);
1H-NMR (DMSO): δ: 5.46 (s, 2H), 5.96 (s, 2H), 6.12 (s, 2H), 6.43-6.45 (d, 1H), 6.59 (s, 1H), 6.79-6.81 (d, 1H), 7.06-7.08 (d, 1H), 7.22-7.26 (m, 4H), 7.45-7.47 (t, 1H), 7.67-7.69 (t, 1H).
2, active testing is implemented
The present invention has measured the inhibiting rate of this compounds to yeast methionine(Met) peptase (ScMetAP1).
Experiment purpose:
Methionine(Met) peptase (MetAP) is the proteolytic enzyme that extensively is present in a kind of necessity in prokaryotic organism (as intestinal bacteria) and the eukaryote living things systems such as (as yeast, Mammalss), its physiological function mainly is the shearing that participates in new synthetic proteins N end methionine(Met), and there is important effect correct location and physiological degraded in vivo biological activity of albumen, the cell for keeping.
Experimental technique:
ScMetAP1 can hydrolysis the thioester key of synthetic substrate Met-S-C-Phe, product Met-SH rapidly with excessive DTNB
Reaction, the 3-hydroxyl of generation-4-nitro thio phenyl phenates has absorption at the 412nm place, changes to determine enzymic activity by the photoabsorption that detects the 412nm place.
Experimental result:
2-substituted aryl-1-substituted benzyl benzimidazole compound sees Table 1 to the inhibiting rate of methionine(Met) peptase:
Table 1 compound is to the inhibiting rate of methionine(Met) peptase
Claims (4)
1. the synthetic method of 2-substituted aryl-1-substituted benzyl benzimidazole compound, it is characterized in that: in reactor, add the O-Phenylene Diamine compound, stirring down, adding weight is O-Phenylene Diamine compound 30-100 water alcohol mixed solvent doubly, add aromatic aldehyde again, the mol ratio of described O-Phenylene Diamine compound and aromatic aldehyde is 1: 2.0-2.5; Then heating, the back of waiting to reflux adds weak acid class catalyzer; Continue back flow reaction 30～90min, finish reaction; Then reaction mixture is poured in the frozen water stir successively, suction filtration, washing, ethyl alcohol recrystallization, obtain 2-substituted aryl-1-substituted benzyl benzimidazole compound.
2. synthetic method according to claim 1 is characterized in that: described weak acid class catalyzer is an oxalic acid, perhaps is oxalate and sour mixture.
3. synthetic method according to claim 1 is characterized in that: described water alcohol mixed solvent is the mixing solutions of second alcohol and water.
4. the purposes of the 2-of a claim 1 substituted aryl-1-substituted benzyl benzimidazole compound is characterized in that: this compound is as the inhibitor of first sulphamide peptase.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603776A (en) * | 2012-02-16 | 2012-07-25 | 哈尔滨工业大学 | Organic light-emitting material 2-(benzimidazolyl)-6-methoxyl-pyridine zinc complex and preparation method thereof |
| CN103435552A (en) * | 2013-06-28 | 2013-12-11 | 浙江工业大学 | 1,2-disubstituted benzimidazole compound preparation method |
| CN103755642A (en) * | 2013-11-18 | 2014-04-30 | 成都理工大学 | Synthetic method of 2-aryl benzimidazole |
| CN112194654A (en) * | 2020-08-28 | 2021-01-08 | 贵州大学 | Benzimidazolium-containing myricetin derivative, preparation method and application |
-
2010
- 2010-01-22 CN CN201010101207A patent/CN101759686A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603776A (en) * | 2012-02-16 | 2012-07-25 | 哈尔滨工业大学 | Organic light-emitting material 2-(benzimidazolyl)-6-methoxyl-pyridine zinc complex and preparation method thereof |
| CN103435552A (en) * | 2013-06-28 | 2013-12-11 | 浙江工业大学 | 1,2-disubstituted benzimidazole compound preparation method |
| CN103755642A (en) * | 2013-11-18 | 2014-04-30 | 成都理工大学 | Synthetic method of 2-aryl benzimidazole |
| CN112194654A (en) * | 2020-08-28 | 2021-01-08 | 贵州大学 | Benzimidazolium-containing myricetin derivative, preparation method and application |
| CN112194654B (en) * | 2020-08-28 | 2022-11-08 | 贵州大学 | Benzimidazole-containing myricetin derivative, preparation method and application |
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Open date: 20100630 |