CN105198819B - The synthesis technique of the formaldehyde of benzimidazole 2 - Google Patents
The synthesis technique of the formaldehyde of benzimidazole 2 Download PDFInfo
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- CN105198819B CN105198819B CN201510612984.3A CN201510612984A CN105198819B CN 105198819 B CN105198819 B CN 105198819B CN 201510612984 A CN201510612984 A CN 201510612984A CN 105198819 B CN105198819 B CN 105198819B
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- formaldehyde
- benzimidazole
- phenylenediamine
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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
- C07D235/12—Radicals substituted by oxygen atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of synthesis technique of the formaldehyde of benzimidazole 2, comprise the following steps：Using hydroxyapatite powder as catalyst, using 46 58 DEG C of hot water as solvent, reacted using o-phenylenediamine and glyoxalic acid as raw material, the mol ratio of the o-phenylenediamine and glyoxalic acid is 1:(1~1.2), reaction time are 2 10 hours, and reaction temperature is 46 58 DEG C, after reaction terminates, filters while hot, filtrate is cooled into 0~4 DEG C, there is white crystals precipitation, and filtering is crystallized, and is dried, is produced the formaldehyde of benzimidazole 2.The raw material and catalyst that synthetic method provided by the invention uses easily obtain, and cost is low；100 DEG C are not needed in operating procedure, 46 58 DEG C of reaction condition is relatively mild；Post processing is filtered, cooled down, refiltering and can obtain the formaldehyde of target product benzimidazole 2, simple to operate, therefore, suitable for the industrial formaldehyde of extensive synthesizing benzimidazole 2.
Description
Technical field
The present invention relates to a kind of synthesis technique of benzimidizole derivatives, and in particular to a kind of benzimidazolyl-2 radicals-formaldehyde
Synthesis technique.
Background technology
Benzimidazoles compound is a kind of Benzoheterocyclic compounds containing two nitrogen-atoms, benzimidizole derivatives and
Its metal complex has good bioactivity, can be used as pharmaceutical intermediate, prepares the anthelmintic drug of people, animal, imidazole ring-containing
Benzimidazole and its derivative because it has special structure, physiologically active and reactivity, in anticancer, antimycotic, town
Pain anti-inflammatory, antirheumatic, expelling parasite etc. have critically important medical value, and application is quite varied, therefore, benzimidazole in decades
It is still very active so far and its synthesis and application study of derivative are never interrupted.Due to the excellent spy of benzimidizole derivatives
Property and extensive use, therefore the synthesis of the derivatives of the research of such compound synthesis method, particularly 1 and 2 substitutions is ground
Study carefully significant and application value.
Pay synthetic method that red flower bud et al. discloses 2- ethyl benzo imidazoles (" 2-Ethyl-Benzimidazole
Synthesis ",《Huadong Geology College's journal》, 2000,23 (4):3473), it is using o-phenylenediamine and propionic acid as raw material, and phosphoric acid is catalysis
Agent, the mol ratio of raw material is 1:2.5, the reaction time is 2 hours, and reaction temperature is about 100 DEG C, when phosphoric acid dosage is 1.5mL, most
The yield of whole 2- ethyl benzo imidazoles is 78%, is that raw material and catalyst are easier to obtain the advantages of this method, and operating procedure is simple,
There is certain application value in synthesis 2- ethyl benzo imidazoles field.
Although above-mentioned prior art discloses a kind of synthetic method of 2- substituted benzimidazoles derivative, this hair is being realized
During bright, inventor has found that the technical scheme of above-mentioned prior art can not be directly applied for benzo miaow according to similar principle
The synthesis of azoles -2- formaldehyde.
Therefore, there is further improvement and optimization and need in the synthetic method for above-mentioned 2- substituted benzimidazoles derivative
Ask, smoothly to obtain benzimidazolyl-2 radicals-formaldehyde, this is exactly the power that the present invention is accomplished and starting point place.
The content of the invention
In order to overcome above-mentioned technical problem existing for prior art, after largely furtheing investigate, so as to provide
A kind of synthesis technique of benzimidazolyl-2 radicals-formaldehyde.
The present invention is achieved through the following technical solutions, a kind of synthesis technique of benzimidazolyl-2 radicals-formaldehyde, including following step
Suddenly：Using hydroxyapatite powder as catalyst, using 46~58 DEG C of hot water as solvent, entered using o-phenylenediamine and glyoxalic acid as raw material
Row reaction, the mol ratio of the o-phenylenediamine and glyoxalic acid is 1:(1~1.2), reaction time are 2~10 hours, reaction temperature
For 46-58 DEG C, after reaction terminates, to filter while hot, filtrate is cooled to 0~4 DEG C, there is white crystals precipitation, filtering is crystallized,
Dry, produce benzimidazolyl-2 radicals-formaldehyde.
Preferably, the mol ratio of the o-phenylenediamine and hydroxyapatite powder is 1:(0.01~0.2), further preferably
, the mol ratio of the o-phenylenediamine and hydroxyapatite powder is 1:0.08.
Preferably, the reaction temperature is 52 DEG C.
The reaction equation of the present invention is as follows.
Compared with prior art, the present invention has the advantages that:The raw material that synthetic method provided by the invention uses
Easily obtained with catalyst, cost is low；The extreme temperatures such as 100 DEG C are not needed in operating procedure, 46-58 DEG C of reaction condition is relatively warm
Be advantageous to safe operation and energy-conservation；Post processing filter, cool down, refilter can obtain target product benzimidazolyl-2 radicals-
Formaldehyde, post-processing operation is simple, therefore, suitable for industrial extensive synthesizing benzimidazole -2- formaldehyde.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the present invention
Protection domain.
Embodiment 1
The present embodiment is related to a kind of synthesis technique of benzimidazolyl-2 radicals-formaldehyde, comprises the steps of：
Using the hydroxyapatite powder 0.008mol of 200 mesh as catalyst, using 52 DEG C of hot water 100mL as solvent, with
0.1mol o-phenylenediamines and 0.11mol glyoxalic acids are that raw material is reacted, and the reaction time is 6 hours, and reaction temperature is 52 DEG C, instead
After should terminating, filter while hot, filtrate is cooled to 2 DEG C, there is white crystals precipitation, filtering is crystallized, and 35 DEG C were dried in vacuo
At night, produce benzimidazolyl-2 radicals-formaldehyde 11.9g, yield 81%, purity 99.6%, MS:M/z=146 (M+),1H NMR(DMSO,
500MHz)δ:(11.03 s, 1H), 10.15 (s, 1H), 8.24 (d, J=8.4Hz, 1H), 8.01 (d, J=8.5Hz, 1H),
7.65-7.58(m,2H)。
Embodiment 2
Using the hydroxyapatite powder 0.001mol of 200 mesh as catalyst, using 46 DEG C of hot water 100mL as solvent, with
0.1mol o-phenylenediamines and 0.12mol glyoxalic acids are that raw material is reacted, and the reaction time is 10 hours, and reaction temperature is 46 DEG C,
After reaction terminates, filter while hot, filtrate is cooled to 4 DEG C, there is white crystals precipitation, filtering is crystallized, 35 DEG C of vacuum drying
Overnight, benzimidazolyl-2 radicals-formaldehyde 11.6g, yield 79%, purity 99.2%, MS are produced:M/z=146 (M+),1H NMR(DMSO,
500MHz)δ:11.02 (s, 1H), 10.19 (s, 1H), 8.24 (d, J=8.5Hz, 1H), 8.03 (d, J=8.5Hz, 1H),
7.66-7.54(m,2H)。
Embodiment 3
Using the hydroxyapatite powder 0.02mol of 200 mesh as catalyst, using 58 DEG C of hot water 100mL as solvent, with
0.1mol o-phenylenediamines and 0.1mol glyoxalic acids are that raw material is reacted, and the reaction time is 2 hours, and reaction temperature is 58 DEG C, instead
After should terminating, filter while hot, filtrate is cooled to 0 DEG C, there is white crystals precipitation, filtering is crystallized, and 35 DEG C were dried in vacuo
At night, produce benzimidazolyl-2 radicals-formaldehyde 11.5g, yield 78%, purity 98.9%, MS:M/z=146 (M+),1H NMR(DMSO,
500MHz)δ:11.04 (s, 1H), 10.17 (s, 1H), 8.24 (d, J=8.5Hz, 1H), 8.02 (d, J=8.6Hz, 1H),
7.62-7.58(m,2H)。
Comparative example 1
The difference of this comparative example and embodiment 1 is：The phosphorus pentoxide for being changed to 0.008mol is catalyst, is finally obtained
Solid crystal 11.6g, MS:M/z=164 (M+), elementary analysis：C 58.4% (theoretical value 58.5%), H 4.9% (theoretical value
4.8%), O 19.6% (theoretical value 19.5%), N 17.1% (theoretical value 17.2%), chemical formula C8H8N2O2(compound 3
Chemical formula be C8H8N2O2, molecular weight 164), the product for illustrating finally to obtain is midbody compound (3), is produced without target
The generation of thing benzimidazolyl-2 radicals-formaldehyde.
Comparative example 2
The difference of this comparative example and embodiment 2 is：The phosphoric acid for being changed to 0.001mol is catalyst, and it is brilliant finally to obtain solid
Body 11.2g, MS:M/z=164 (M+), elementary analysis：C 58.3% (theoretical value 58.5%), H 4.7% (theoretical value 4.8%),
O 19.7% (theoretical value 19.5%), N 17.0% (theoretical value 17.2%), chemical formula C8H8N2O2(the chemical formula of compound 3
For C8H8N2O2, molecular weight 164), the product for illustrating finally to obtain is midbody compound (3), without target product benzo miaow
The generation of azoles -2- formaldehyde.
Comparative example 3
The difference of this comparative example and embodiment 3 is：The phosphoric acid for being changed to 0.02mol is catalyst, and it is brilliant finally to obtain solid
Body 10.7g, MS:M/z=164 (M+), elementary analysis：C 58.2% (theoretical value 58.5%), H 4.8% (theoretical value 4.8%),
O 19.4% (theoretical value 19.5%), N 17.0% (theoretical value 17.2%), chemical formula C8H8N2O2(the chemical formula of compound 3
For C8H8N2O2, molecular weight 164), the product for illustrating finally to obtain is midbody compound (3), not target product benzo
The generation of imidazoles -2- formaldehyde.
Analysis of conclusion
Implement above-described embodiment 1-3 and comparative example 1-3 respectively, and count the yield and purity of benzimidazolyl-2 radicals-formaldehyde.It is real
The yield an of 1-3 (hydroxyapatite powder is catalyst) acquisition things benzimidazolyl-2 radicals-formaldehyde is applied 80% or so, and is contrasted
After example 1-3 catalyst uses phosphorus pentoxide or phosphoric acid instead, the generation of benzimidazolyl-2 radicals-formaldehyde, does not illustrate hydroxy-apatite
Stone powder has vital influence, especially o-phenylenediamine as catalyst on the generation for generating benzimidazolyl-2 radicals-formaldehyde
Mol ratio with hydroxyapatite powder is 1:More prominent, o-phenylenediamine and hydroxylapatite powder are influenceed when (0.01~0.2)
The mol ratio at end is 1:It is better when 0.08, therefore, suitable for industrial extensive synthesizing benzimidazole -2- formaldehyde.
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring the substantive content of the present invention.
Claims (1)
1. a kind of synthesis technique of benzimidazolyl-2 radicals-formaldehyde, it is characterised in that comprise the following steps：With hydroxyapatite powder
For catalyst, using 46~58 DEG C of hot water as solvent, reacted using o-phenylenediamine and glyoxalic acid as raw material, the o-phenylenediamine
Mol ratio with glyoxalic acid is 1:(1~1.2), reaction time are 2~10 hours, and reaction temperature is 46~58 DEG C, and reaction terminates
Afterwards, filter while hot, filtrate be cooled to 0~4 DEG C, there is a white crystals precipitation, filtering is crystallized, drying, produce benzimidazole-
2- formaldehyde；
The mol ratio of the o-phenylenediamine and the hydroxyapatite powder is 1:0.08.
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| KR102653426B1 (en) | 2017-11-13 | 2024-03-29 | 에코랍 유에스에이 인코퍼레이티드 | A novel single-reactor homogeneous method for large-scale production of 2-substituted benzimidazoles |
| US20230192700A1 (en) | 2020-03-06 | 2023-06-22 | Bayer Aktiengesellschaft | Pyrazolopyrazines acting on cancers via inhibition of cdk12 |
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| CN104211632B (en) * | 2013-05-31 | 2016-12-28 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 2 indolone derivatives with tyrosine-kinase enzyme inhibition activity and preparation method and application |
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