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Preparation method of aryl-substituted pyrimidinamine acylated derivative

A technology for pyrimidine amide and derivatives, which is applied in the field of preparation of aryl-substituted pyrimidine amide acylation derivatives, can solve problems such as unreported preparation methods, and achieve the effects of easy availability of raw materials, huge economic value and simple operation.

Inactive Publication Date: 2018-11-13
湖北欣瑞康医药科技有限公司
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Problems solved by technology

However, the multiple efflux resistance mechanism of bacteria is produced by the ABC superfamily P-gp efflux system and the RND family AcrAB-TolC efflux system, and these two efflux systems are now used as research objects to design aryl-substituted The preparation method of the efflux pump inhibitor of pyrimidine amine acylated derivatives has not been reported yet.

Method used

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  • Preparation method of aryl-substituted pyrimidinamine acylated derivative
  • Preparation method of aryl-substituted pyrimidinamine acylated derivative
  • Preparation method of aryl-substituted pyrimidinamine acylated derivative

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preparation example Construction

[0024] The preparation method of aryl-substituted pyrimidine amine acylated derivatives of the present invention comprises the preparation of 1-(2-thienyl)-3-(4-(4-methylpiperazinyl)phenyl)-propenone, 4- (2-thienyl)-6-(4-(4-methylpiperazinyl) phenyl)-pyrimidin-2-amine preparation and 4-(2-thienyl)-6-(4-(4- The preparation of methylpiperazinyl) phenyl)-pyrimidine-2-acylated derivative amine, the specific preparation steps are as follows:

[0025] 1) the preparation of 1-(2-thienyl)-3-(4-(4-methylpiperazinyl) phenyl)-propenone, its synthetic route is:

[0026]

[0027] Specifically: add alkali and organic solvent into the reaction flask, stir evenly at room temperature, then add 4-(4-methylpiperazinyl)benzaldehyde, slowly add 2-acetylthiophene, at a temperature of 30-60°C Stir the reaction, monitor the end point of the reaction by thin-layer chromatography, and filter with suction to obtain 1-(2-thienyl)-3-(4-(4-methylpiperazinyl)phenyl)-propenone as a light yellow solid pow...

Embodiment 1

[0043] (1), the preparation of 1-(2-thienyl)-3-(4-(4-methylpiperazinyl) phenyl)-propenone:

[0044] Add 1.0 mol of sodium hydroxide and 400 ml of anhydrous methanol into the reaction flask, stir at room temperature, then add 0.1 mol of 4-(4-methylpiperazinyl)benzaldehyde, and slowly add 0.1 mol of 2-acetylthiophene dropwise. , Stir the reaction at 40°C, monitor the end point of the reaction by thin-layer chromatography, cool to room temperature, and filter with suction to obtain a light yellow solid powder with a yield of 80-85%.

[0045] (2), the preparation of 4-(2-thienyl)-6-(4-(4-methylpiperazinyl)phenyl)-pyrimidine-2-amine:

[0046] Add 0.8mol of sodium hydroxide and 500ml of anhydrous methanol into the reaction flask, stir at room temperature, and then add 1-(2-thienyl)-3-(4-(4-methylpiperazinyl)phenyl)-propene 0.1 mol of ketone and 0.12 mol of guanidine hydrochloride were heated to 65°C and stirred for reaction. The end point of the reaction was monitored by thin-layer...

Embodiment 2

[0052] (1), the preparation of 1-(2-thienyl)-3-(4-(4-methylpiperazinyl) phenyl)-propenone:

[0053] Add 1.25 mol of sodium carbonate and 500 ml of absolute ethanol into the reaction flask, stir at room temperature, then add 0.1 mol of 4-(4-methylpiperazinyl)benzaldehyde, slowly add 0.2 mol of 2-acetylthiophene dropwise, Stir the reaction at 56°C, monitor the end point of the reaction by thin-layer chromatography, cool to room temperature, and filter with suction to obtain a light yellow solid powder with a yield of 80-84%.

[0054] (2), the preparation of 4-(2-thienyl)-6-(4-(4-methylpiperazinyl)phenyl)-pyrimidine-2-amine:

[0055] Add 1.125mol of sodium hydroxide, 300ml of anhydrous methanol and 200ml of anhydrous ethanol into the reaction flask, stir at room temperature, and then add 1-(2-thienyl)-3-(4-(4-methylpiperazinyl) 0.1mol of phenyl)-propenone and 0.12mol of guanidine hydrochloride, heated to 80°C and stirred for reaction, monitored the end point of the reaction by t...

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Abstract

The invention discloses a preparation method of an aryl-substituted pyrimidinamine acylated derivative. The preparation method comprises the following steps: preparation of 1-(2-thienyl)-3-(4-(4-methylpiperazinyl)phenyl)-acrylketone, preparation of 4-(2-thienyl)-6-(4-(4-methylpiperazinyl)phenyl)-pyrimidin-2-amine and preparation of 4-(2-thienyl)-6-(4-(4-methylpiperazinyl)phenyl)pyrimidin-2-acylated derivative amine; in the preparation method, an ABC superfamily P-gp efflux system and an RND family AcrAB-TolC efflux system are used as research objects, an efflux pump inhibitor of the aryl-substituted pyrimidinamine acylated derivative is designed, and 4-(4-methylpiperazinyl)benzaldehyde is used as a main raw material, to perform three-step reaction of Michael addition elimination, cyclization and acylation to obtain a target compound. The preparation method has the advantages of high selectivity, simple operation, easy availability of raw materials and mild conditions, hopes that the derivative can exert antibacterial and synergistic activity, and has great economic value and far-reaching social significance.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of an aryl-substituted pyrimidinamide acylated derivative. Background technique [0002] On April 30, 2014, WHO conducted a survey based on data from 114 countries and released a report stating that antibiotic-resistant bacteria are spreading to all parts of the world. The report advises healthcare workers to keep antibiotic prescribing to the minimum necessary. At the same time, ordinary patients are urged to use antibiotics only when prescribed by doctors. Bacterial resistance to antibiotics has become a rapidly growing problem in the United States. The World Health Organization has warned that this is one of the most significant threats to global health. Due to the indiscriminate use of antibiotics, superbugs have been found in Europe, Canada and China. So-called superbugs could kill a patient every three seconds by 2050 un...

Claims

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Application Information

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IPC IPC(8): C07D409/04
CPCC07D409/04
Inventor 刘明星戴康吴建宏
Owner 湖北欣瑞康医药科技有限公司
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