CN109096205B - Synthesis method of benzimidazole compound - Google Patents
Synthesis method of benzimidazole compound Download PDFInfo
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- CN109096205B CN109096205B CN201811181219.0A CN201811181219A CN109096205B CN 109096205 B CN109096205 B CN 109096205B CN 201811181219 A CN201811181219 A CN 201811181219A CN 109096205 B CN109096205 B CN 109096205B
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- phenylenediamine
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- 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
Abstract
The invention discloses a synthesis method of a benzimidazole compound, which comprises the following synthetic route:
Description
Technical Field
The invention belongs to the field of synthesis of organic heterocyclic compounds, and particularly relates to a synthesis method of a benzimidazole compound.
Background
Benzimidazoles are a very important class of organic heterocyclic compounds, which have a variety of biological and pharmacological activities, such as: blood coagulation, anticancer, spasmolysis, anti-allergy, etc., and benzimidazole derivatives are also important building blocks of many natural products. Therefore, in recent years, the research on benzimidazole derivatives has been more and more intensive, and has become a hot spot in the research field of organic synthetic chemistry.
In the prior art, a common method for synthesizing benzimidazole derivatives is to perform a dehydration cyclization reaction on o-phenylenediamine and aromatic aldehyde. Strongly acidic conditions are generally required, and sometimes very high reaction temperatures are required, resulting in less than optimal yields. The common synthetic method is to add an oxidant, such as nitrobenzene, p-benzoquinone, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ), manganese dioxide, sodium thiosulfate and the like. The catalytic synthesis of benzimidazole by these oxidants usually needs to be carried out at high temperature, and the conditions are harsh, the operation is complex, and the product post-treatment is cumbersome. In addition, the metal indium compound, the rare earth metal ytterbium compound, tannic acid and the like are used as catalysts to synthesize the benzimidazole compound, although the benzimidazole compound can effectively catalyze the reaction of o-phenylenediamine and aromatic aldehyde to generate the benzimidazole compound, the problems are more or less, such as expensive catalyst, difficult catalyst preparation, harsh reaction conditions, complex post-treatment operation, incapability of recycling the catalyst, residual catalyst harmfulness and the like.
Therefore, there is a need to develop a method for synthesizing benzimidazole compounds, which has high synthesis efficiency, simple operation and environmental protection.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for synthesizing a benzimidazole compound, which has the characteristics of high synthesis efficiency, simple operation and environmental protection.
The technical scheme adopted by the invention is as follows: a method for synthesizing a benzimidazole compound,
the synthetic route of the synthetic method is as follows:
the invention adopts L-carnitine as a catalyst, which is a weight-reducing medicine with relatively low toxicity and safety. Meanwhile, based on the quaternary ammonium salt N positive ion and carboxyl negative ion structure in the L-carnitine molecule, a transition state intermediate is formed smoothly in the catalysis process, and a target molecule is obtained through oxidation, wherein the catalysis principle is as follows:
the synthesis method comprises the following steps:
1) adding substituted o-phenylenediamine (I), aromatic aldehyde (II) and L-carnitine into a solvent, and carrying out heating reaction to obtain a crude product;
2) filtering the crude product obtained in the step 1), collecting solid substances, and drying to obtain a benzimidazole compound (III);
ar of the aromatic aldehyde is a benzene ring with substituent groups on the ortho, meta and/or para positions, and the substituent groups comprise halogen, methoxy and nitro;
r of the substituted o-phenylenediamine comprises hydrogen and a nitro group.
Preferably, the synthesis method further comprises a step of recrystallizing the dried benzimidazole compound after the step 2).
More specifically, the method for synthesizing the benzimidazole compound comprises the following steps:
1) adding substituted o-phenylenediamine, aromatic aldehyde and L-carnitine into a solvent, and carrying out heating reaction to obtain a crude product;
2) filtering the crude product obtained in the step 1), collecting solid substances, drying, and recrystallizing with ethanol to obtain the benzimidazole compound.
Preferably, in the step 1), the molar ratio of the substituted o-phenylenediamine to the aromatic aldehyde is 1-3: 1-3. More preferably, the molar ratio of substituted o-phenylenediamine to aromatic aldehyde is 1: 1.
Preferably, in the step 1), the molar ratio of the substituted o-phenylenediamine to the L-carnitine is 1: 0.05-0.15. More preferably, the molar ratio of the substituted o-phenylenediamine to the l-carnitine is 1: 0.1.
Preferably, in step 1), the solvent is one or more selected from the group consisting of n-hexane, cyclohexane, 1, 2-dichloroethane, ethanol, chloroform and water. More preferably, in step 1), the solvent is 95% ethanol.
Preferably, in the step 1), the ratio of the mole number of the substituted o-phenylenediamine to the volume of the solvent is 1mmol:3-10 mL. More preferably, the ratio of the number of moles of the substituted o-phenylenediamine to the volume of the solvent is 1mmol:5 mL.
Preferably, in the step 1), the heating reaction temperature is 25-80 ℃, and the heating reaction time is 1-4 h. More preferably, the heating reaction temperature is 60 ℃ and the heating reaction time is 2 h.
Preferably, in the step 2), the drying temperature is 60-120 ℃, and the drying time is 1-5 h. More specifically, the drying temperature is 90 ℃, and the drying time is 1 h; or the drying temperature is 100 ℃, and the drying time is 2 h.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention creatively prepares the benzimidazole compound by using the substituted o-phenylenediamine, the aromatic aldehyde and the L-carnitine under the heating condition, the synthesis method uses the substituted o-phenylenediamine and the aromatic aldehyde as starting raw materials, has simple preparation and convenient operation, does not need to separate and purify intermediates in a series of conversion processes except final products, uses a small amount of catalyst, saves the cost and the input amount of labor force, and provides an important means for preparing the benzimidazole compound in a green, simple and efficient way.
2. The catalysis principle of the catalyst L-carnitine is that quaternary ammonium salt N positive ions and carboxyl negative ions in molecules form a transition state intermediate smoothly in the catalysis process, and finally target molecules are obtained through oxidation. The catalyst is a commercial product, has the advantages of easily available source, low price, mild and controllable reaction conditions, high synthesis efficiency, repeated utilization for many times and simple post-treatment. Moreover, benzimidazole compounds are important clinical drugs, and the residue of the catalyst may bring harm to patients. The catalyst L-carnitine adopted by the invention is a recognized weight-reducing nutritional supplement, is safe and can be taken, and even if a small amount of L-carnitine residues are left after post-treatment, the L-carnitine does not bring harm to the body of a patient.
3. The method has the advantages of cheap and easily-obtained starting raw materials, relatively mild reaction conditions, high synthesis efficiency and simple and convenient post-treatment operation, and the synthesized benzimidazole compound has the yield of 90-98% and the purity of 92-99%, has good practical value and social and economic efficiency, and has good reference significance for process development of similar products and downstream products.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), p-chlorobenzaldehyde (141mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 5mL of 95% ethanol, and heating and reacting at 60 ℃ for 2h under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), drying at the temperature of 90 ℃ for 1h, and recrystallizing with ethanol to obtain a white solid with the yield of 97% and the purity of 99%.
The product was subjected to nmr detection and principal element analysis with the following data:
1H-NMR(400MHz,DMSO-d6)：δ13.03(s,1H),8.23(d,2H,J＝8.5Hz),7.70-7.63(m,3H),7.55(d,1H,J＝7.2Hz),7.26-7.23(m,2H)；
13C NMR(100MHz,DMSO-d6):δ149.8,143.5,134.5,134.3,129.0,128.7,128.1,122.6,121.8,118.7,111.3；
Anal.Calcd.for C13H9ClN2:C 68.28,H 3.97,N 12.25.Found:C 68.23,H 4.12,N 12.28。
the nuclear magnetic resonance detection and the main element analysis result show that the obtained product is 2- (4-chlorphenyl) -1H-benzo [ d ] imidazole.
Example 2
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding 4-nitro o-phenylenediamine (153mg, 1.0mmo1), p-chlorobenzaldehyde (141mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 5mL of 95% ethanol, and heating to react for 2h at 60 ℃ under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), drying at the temperature of 60 ℃ for 2h, and recrystallizing with ethanol to obtain a yellow solid with the yield of 98% and the purity of 99%.
The product was subjected to nmr detection and principal element analysis with the following data:
1H-NMR(400MHz,DMSO-d6)：δ13.66(s,1H),8.81(s,1H),8.12(d,J＝9.0Hz,1H),8.01(d,J＝9.0Hz,1H),7.52(d,J＝9.0Hz,2H),7.43(d,J＝9.0Hz,2H)；
13C NMR(100MHz,DMSO-d6)δ158.4,151.1,135.9,135.2,133.3,131.6,129.9,125.0,124.4,113.2,112.8；
Anal.Calcd.for C13H8ClN3O2:C 57.05,H 2.95,N 15.35.Found:C 57.16,H 2.76,N 15.33。
the nuclear magnetic resonance detection and the main element analysis result show that the obtained product is 2- (4-chlorphenyl) -5-nitryl-1H-benzo [ d ] imidazole.
Example 3
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), p-methoxybenzaldehyde (136mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 5mL of 95% ethanol, and heating and reacting at 60 ℃ for 1h under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), drying at the temperature of 70 ℃ for 3h, and recrystallizing with ethanol to obtain a white solid with the yield of 95% and the purity of 99%.
The product was subjected to nmr detection and principal element analysis with the following data:
1H NMR(400MHz，DMSO-d6)：δ12.75(s,1H),8.09(d,2H,J＝8.7Hz),7.55(m,2H),7.19-7.16(m,2H),7.10(d,2H,J＝8.8Hz),3.83(s,3H)；
13C NMR(100MHz,DMSO-d6)：δ160.3,151.0,143.4,134.7,127.7,122.3,121.8,121.4,118.1,114.0,110.8,55.1；
Anal.Calcd.for C14H12N2O:C 74.98,H 5.39,N 12.49.Found:C 74.79,H 5.21,N 12.46。
the nuclear magnetic resonance detection and the main element analysis result show that the obtained product is 2- (4-methoxyphenyl) -1H-benzo [ d ] imidazole.
Example 4
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), p-chlorobenzaldehyde (141mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 5mL of cyclohexane, and heating and reacting at 80 ℃ for 1h under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), and drying at the temperature of 60 ℃ for 4H to obtain the product 2- (4-chloro-phenyl) -1H-benzo [ d ] imidazole, wherein the yield is 90% and the purity is 94%.
Example 5
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding 4-nitrophthalenediamine (306mg, 2.0mmo1), 4-bromobenzaldehyde (555mg, 3.0mmo1) and L-carnitine (48.4mg, 0.3mmol) into a mixed solvent of 8mL of ethanol and 8mL of water, and heating and reacting for 4 hours at 40 ℃ under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), drying for 2H at the temperature of 100 ℃, and recrystallizing by using ethanol to obtain the product 2- (4-bromophenyl) -5-nitro-1H-benzo [ d ] imidazole, wherein the yield is 97%, and the purity is 98%.
Example 6
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (324mg, 3.0mmo1), 3-nitrobenzaldehyde (151mg, 1.0mmo1) and L-carnitine (48.4mg, 0.3mmol) into 30mL of n-hexane, and heating and reacting for 3h at 25 ℃ under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), and drying at the temperature of 120 ℃ for 1H to obtain the product 2- (3-nitrophenyl) -1H-benzo [ d ] imidazole, wherein the yield is 96% and the purity is 95%.
Example 7
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (216mg, 2.0mmo1), 2-methoxybenzaldehyde (136mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 6mL of 1, 2-dichloroethane, and heating and reacting at 50 ℃ for 1h under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), and drying at the temperature of 70 ℃ for 5H to obtain the product 2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole, wherein the yield is 95% and the purity is 92%.
Example 8
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), 2, 4-dichlorobenzaldehyde (175mg, 1.0mmo1) and L-carnitine (16.1mg, 0.1mmol) into 5mL of 95% ethanol, and heating to react for 3h at 60 ℃ under electromagnetic stirring to obtain a crude product;
2) filtering the crude product obtained in the step 1), drying at the temperature of 90 ℃ for 1H, and recrystallizing by using ethanol to obtain the product 2- (2, 4-dichlorophenyl) -1H-benzo [ d ] imidazole, wherein the yield is 95% and the purity is 97%.
Comparative example 1
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), 4-methoxybenzaldehyde (136mg, 1.0mmo1) and tannic acid (48.8mg, 0.03mmol) into 5mL of 95% ethanol, and heating and reacting at 60 ℃ for 1h under electromagnetic stirring;
2) pouring the mixture subjected to the heating reaction in the step 1) into water to obtain flocculent precipitate, standing in a refrigerator for 2 hours, taking out, filtering, drying, and recrystallizing with ethanol to obtain the product 2- (4-methoxyphenyl) -1H-benzo [ d ] imidazole, wherein the yield is 92% and the purity is 90%.
Comparative example 2
A method for synthesizing benzimidazole compounds has the following reaction formula:
the method comprises the following steps:
1) adding o-phenylenediamine (108mg, 1.0mmo1), p-chlorobenzaldehyde (141mg, 1.0mmo1) and tannic acid (49.8mg, 0.03mmol) into 5mL of cyclohexane, and heating to react at 80 ℃ for 7h under electromagnetic stirring;
2) pouring the mixture subjected to the heating reaction in the step 1) into water to obtain flocculent precipitate, standing in a refrigerator for 2 hours, taking out, filtering, drying, and recrystallizing by using ethanol to obtain the product 2- (4-chlorophenyl) -1H-benzo [ d ] imidazole, wherein the yield is 35% and the purity is 90%.
Claims (8)
1. A method for synthesizing benzimidazole compounds is characterized in that,
the synthetic route of the synthetic method is as follows:
the synthesis method comprises the following steps:
1) adding substituted o-phenylenediamine (I), aromatic aldehyde (II) and L-carnitine into a solvent, and carrying out heating reaction to obtain a crude product;
2) filtering the crude product obtained in the step 1), collecting solid substances, and drying to obtain a benzimidazole compound (III);
ar of the aromatic aldehyde is a benzene ring with substituent groups on the ortho, meta and/or para positions, and the substituent groups are selected from halogen, methoxy and nitro;
r of the substituted o-phenylenediamine is selected from hydrogen and nitro;
the solvent is selected from one or more of n-hexane, cyclohexane, 1, 2-dichloroethane, ethanol and chloroform;
the temperature of the heating reaction is 25-80 ℃.
2. The synthesis method according to claim 1, characterized in that after the step 2), the synthesis method further comprises a step of recrystallizing the dried benzimidazole compound.
3. The synthesis method according to claim 1 or 2, wherein in step 1), the molar ratio of the substituted o-phenylenediamine to the aromatic aldehyde is 1-3: 1-3.
4. The synthesis method according to claim 1 or 2, wherein in step 1), the molar ratio of the substituted o-phenylenediamine to the l-carnitine is 1: 0.05-0.15.
5. The method of claim 1, wherein in step 1), the solvent is 95% ethanol.
6. The synthesis method according to claim 1 or 2, wherein in the step 1), the ratio of the mole number of the substituted o-phenylenediamine to the volume of the solvent is 1mmol:3-10 mL.
7. The synthesis method according to claim 1 or 2, wherein in the step 1), the heating reaction time is 1-4 h.
8. The synthesis method according to claim 1 or 2, wherein in the step 2), the drying temperature is 60-120 ℃ and the drying time is 1-5 h.
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| Title |
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| 1,3-Dibromo-5,5-dimethylhydantoin as an efficient homogeneous catalyst for synthesis of benzoxazoles, benzimidazoles，and oxazolo[4,5-b]pyridines;Seyedeh Fatemeh Hojat，等;《Monatsh Chem》;20111231;87-91 * |
| 单宁酸催化的"一锅法"绿色合成苯并咪唑的研究;陈路，等;《五邑大学学报（自然科学版）》;20170228;20-24 * |
| 新型手性相转移催化合成L-苯丙氨酸;吴建一，等;《精细石油化工》;20140131;14-17 * |
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