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Preparation method of medical intermediate dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative

A technology of pyrimidine derivatives and aminobenzimidazole, which is applied in the field of biomedicine, can solve the problems of difficult reuse of catalysts and reaction solvents and low yields, and achieve the goals of ensuring effective production rate, simple recycling and reuse, and shortening reaction time Effect

Active Publication Date: 2020-06-09
东营睿港管道工程有限责任公司
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  • Abstract
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Problems solved by technology

[0005] Aiming at the problems of low yield and difficult reuse of catalysts and reaction solvents in the existing methods for preparing dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivatives, the present invention provides a pharmaceutical intermediate A method for preparing hydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivatives, using ethanol aqueous solution as a reaction solvent and recrystallization solvent, and using magnetic graphene acidic nanomaterials as catalysts to catalyze aromatic aldehydes and β-ketones Ester and 2-aminobenzimidazole reaction to prepare dihydrobenzo [4,5] imidazo [1,2-a] pyrimidine derivatives, high raw material utilization rate, few by-products, high product yield, reaction solvent and Catalysts can be recycled

Method used

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  • Preparation method of medical intermediate dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative
  • Preparation method of medical intermediate dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative
  • Preparation method of medical intermediate dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative

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Experimental program
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Effect test

Embodiment 1

[0033] Such as figure 1 As indicated, add 1.0mmol benzaldehyde, 1.0mmol 2-amino-benzimidazole, 1.05mmol ethyl acetoacetate and 1.45g magnetic Graphene acidic nano material catalyst, stirred evenly at room temperature. Heating and reflux reaction at 80°C for 37 minutes, TLC (thin plate chromatography) detection, the raw material point disappeared, after the reaction was completed, the catalyst was adsorbed with a magnet while the temperature was not lower than 70°C, the remaining reaction solution was cooled to room temperature, and the precipitated The solid was left to stand, filtered with suction, and the filter residue was washed with ethanol and dried under vacuum at 85°C for 3 hours to obtain 4-phenyl-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1, 2-a] Ethyl pyrimidine-3-carboxylate, the purity determined by high performance liquid chromatography was 99.5%, and the calculated yield was 91%. Put the adsorbed catalyst into the filtrate, directly add benzaldehyde, 2-amino-benzim...

Embodiment 2

[0036] Add 1.0mmol benzaldehyde, 1.0mmol 2-amino-benzimidazole, 1.0mmol methyl propionyl acetate and 1.32g magnetic graphene to a 50ml single-necked bottle with a condenser tube and a stirring bar containing 7ml 93% ethanol aqueous solution Acidic nano material catalyst, stir evenly at room temperature. Heating and reflux reaction at 80°C for 32 minutes, TLC (thin plate chromatography) detection, the raw material point disappeared, after the reaction was completed, the catalyst was adsorbed with a magnet while the temperature was not lower than 70°C, the remaining reaction solution was cooled to room temperature, and the precipitated The solid was left to stand, filtered with suction, and the filter residue was washed with ethanol and dried under vacuum at 85°C for 3 hours to obtain 4-phenyl-2-ethyl-1,4-dihydrobenzo[4,5]imidazo[1, 2-a] Pyrimidine-3-methyl carboxylate, the purity determined by high performance liquid chromatography was 99.1%, and the yield was 94%. Put the ads...

Embodiment 3

[0039] Add 1.0mmol p-bromobenzaldehyde, 1.0mmol 2-amino-benzimidazole, 1.0mmol ethyl acetoacetate and 1.35g magnetic graphite Acrylic acid nano material catalyst, stirring at room temperature evenly. Heating and reflux reaction at 80°C for 34 minutes, TLC (thin plate chromatography) detection, the raw material point disappeared, after the reaction was completed, the catalyst was adsorbed with a magnet while the temperature was not lower than 70°C, the remaining reaction solution was cooled to room temperature, and the precipitated The solid was left to stand, filtered with suction, and the filter residue was washed with ethanol and dried under vacuum at 85°C for 3 hours to obtain 4-(4-bromophenyl)-2-methyl-1,4-dihydrobenzo[4,5] Ethyl imidazo[1,2-a]pyrimidine-3-carboxylate has a purity of 99.2% and a yield of 92% as determined by high performance liquid chromatography. Put the adsorbed catalyst into the filtrate, directly add p-bromobenzaldehyde, 2-amino-benzimidazole and ethy...

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Abstract

The invention discloses a preparation method of a medical intermediate, namely a dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative, belonging to the technical field of biological medicines. The method comprises the following steps: taking aromatic aldehyde, beta-keto ester and 2-aminobenzimidazole as raw materials, and carrying out catalytic condensation on the raw materials in ethanol water byvirtue of a magnetic graphene acidic nano-material. The preparation method provided by the invention can effectively overcome the defects of conventional preparation processes, and has the advantagesof high product yield, simple preparation process, mild reaction conditions, high greenization degree of the preparation process, easiness in industrial large-scale application and the like.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically relates to a preparation method of a pharmaceutical intermediate dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivative. Background technique [0002] Pyrimidine compounds are six-membered heterocyclic compounds containing two nitrogen atoms, which widely exist in nature and organisms, and the dihydropyrimidine derivatives are also a very important class of organic compounds, which are the structural units of some natural products. It has a wide range of biological and pharmacological activities, and has a wide range of applications in medicine. For example, it can be used as TIE-2 and VEGFR2 activity inhibitors, protein kinase inhibitors, has activation function and anti-tumor activity on T cells, and can also directly inhibit tyrosine receptor protein kinases and improve cardiovascular activity. In addition, dihydropyrimidine derivatives can also be used as the parent structure t...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 卢蓉蓉
Owner 东营睿港管道工程有限责任公司