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2-(2-hydroxy - substituted phenethyl sulfenyl]-3h-pyrimidin-4-ketone compounds and synthesis method and application thereof

A technology of ketone compounds and phenethyl, which is applied in the field of 2--3H-pyrimidin-4-one compounds and their synthesis, can solve the problems of unsatisfactory bioavailability and poor water solubility, and achieve convenient synthesis and obvious inhibition The effect of action

Inactive Publication Date: 2014-04-16
YUNNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The inventor has been engaged in the research and development of anti-HIV drugs for a long time. In recent years, we have designed and synthesized a series of 2-(substituted phenylcarbonylmethylthio)-4(3H)-pyrimidinone HIV reverse transcriptase inhibitors (see the following compounds 1), in vitro experiments prove that these compounds have higher anti-HIV activity and less cytotoxicity, but poor water solubility and unsatisfactory bioavailability

Method used

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  • 2-(2-hydroxy - substituted phenethyl sulfenyl]-3h-pyrimidin-4-ketone compounds and synthesis method and application thereof
  • 2-(2-hydroxy - substituted phenethyl sulfenyl]-3h-pyrimidin-4-ketone compounds and synthesis method and application thereof
  • 2-(2-hydroxy - substituted phenethyl sulfenyl]-3h-pyrimidin-4-ketone compounds and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of embodiment one β-keto ester (3)

[0030] Put 0.1 mol of substituted diethyl malonate (2) (diethyl methyl malonate, diethyl ethyl malonate) in 150 mL of absolute ethanol, add 0.1 mol of KOH in ethanol, Stir at room temperature for 12 hours, evaporate the solvent under reduced pressure, wash twice with ether or ethyl acetate, and evaporate the solvent again under reduced pressure to obtain monopotassium substituted diethyl malonate, which is directly used in the next reaction.

[0031] Put 0.1 mol of monopotassium substituted diethyl malonate in 150 mL of anhydrous acetonitrile, and add 0.18 mol of anhydrous MgCl in sequence 2 , 0.15mol Et 3 N, stirred at room temperature for 2 hours; 0.048mol of substituted phenylacetic acid / cyclohexylacetic acid (1) was placed in 100mL of anhydrous acetonitrile, and 0.05mol of N,N-carbonyldiimidazole was added batch by batch, reacted for one hour, and then Add the reaction mixture to substituted diethyl malonate mon...

Embodiment 2

[0032] Example 2 Preparation of 5-alkyl-6-(substituted benzyl / cyclohexylmethyl)-2-thio-3H-pyrimidin-4-one (4)

[0033]In a dry reaction flask, add 10 g (0.43 mol) of sodium metal in 300 mL of absolute ethanol in batches, and after the sodium is dissolved and cooled, add 24 g (0.315 mol) of thiourea at one time, and then dropwise add β-keto ester ( 3) 20 mL of ethanol solution, the mixture was heated to reflux for 5-7 hours, TLC traced to the β-keto ester raw material point disappeared, then stopped heating, cooled, evaporated the solvent under reduced pressure, dissolved the residue in 300 mL of water, and used concentrated Adjust the pH value to about 6 with hydrochloric acid, a large amount of white precipitates are produced, filter with suction, wash the filter cake with water, and dry to obtain 5-alkyl-6-(substituted benzyl / cyclohexylmethyl)-2-sulfanyl-3H- Pyrimidin-4-one (4) can be directly used in the next step of target compound synthesis without purification.

Embodiment 3

[0034] Example 3 Preparation of 2-[(substituted phenyl)carbonylmethylthio]-6-substituted benzyl / cyclohexylmethyl-5-alkyl-3H-pyrimidin-4-one compound (5)

[0035] 2mmol of 6-(substituted benzyl / cyclohexylmethyl)-5-alkyl-2-sulfanyl-3H-pyrimidin-4-one (4) and 2mmol of K 2 CO 3 Place in a reaction bottle, add 15 mL of anhydrous N, N-dimethylformamide (DMF), stir at room temperature for 30 min, add 2.2 mmol of each α-bromoacetophenone, stir at room temperature for 12-16 hours, TLC Track until the raw material point disappears, stop the reaction, add 100mL of ice water, a white precipitate is formed, filter with suction, recrystallize with ethanol, part of it needs to be purified by column chromatography to obtain pure product.

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Abstract

The invention provides 2-(2-hydroxy - substituted phenethyl sulfenyl]-3H-pyrimidin-4-ketone compounds and a synthesis method and application thereof, belonging to the technical field of pharmaceuticals. The compounds have a structural general formula shown in the specification, wherein R1 is methyl or ethyl, R2 is hydrogen, methoxyl, fluorine or hydroxyl, and R3 is shown in the specification, wherein X is methoxyl, fluorine or hydroxyl. The invention also relates to a preparation method of the compounds; and the compounds can be used as candidates of medicines for resisting hepatitis C or serve as active components of anti-HCV (hepatitis C virus) medicines of different preparation forms.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to 5-alkyl-2-[2-hydroxyl-2-substituted phenethylsulfur]-6-substituted benzyl / cyclohexylmethyl-3H-pyrimidin-4-one compounds , its synthesis method and use, that is, 2-(2-hydroxyl-2-substituted phenethylthio)-3H-pyrimidin-4-one compounds and their synthesis method and use. Background technique [0002] Hepatitis C is a liver disease that seriously threatens human health caused by hepatitis C virus (HCV). In 1989, HCV was identified as the main pathogen of non-A and non-B hepatitis for the first time. According to the report of the World Health Organization (WHO), in 2000, about 3% of the world's population was infected with this type of virus, and there are about 3 million to 4 million new cases every year, 70% to 90% form chronic infection, 30% Develop progressive liver disease, including cirrhosis or liver cancer. According to reports this year, the number of HCV-infected peopl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/56A61K31/513A61P31/14A61P1/16
Inventor 何严萍夏雪山伍道春冯悦王华李聪
Owner YUNNAN UNIV