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Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof

A technology of dihydropyrimidinone and tetrahydropyridine, applied in the fields of thiotetrahydropyridodihydropyrimidinone derivatives, their preparation and application, to achieve the effects of easy production, convenient post-processing, and convenient post-processing

Inactive Publication Date: 2013-02-06
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, there is no compound that can effectively inhibit the above diseases at the same time

Method used

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  • Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof
  • Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof
  • Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Preparation of 4-phenyl-6-p-fluorobenzyl-8-benzylidene-1,2,5,6-tetrahydropyrido[4,3-d]-3,4-dihydropyrimidine- 2-thione (Ia);

[0058] At room temperature, add 0.16mol methyl acrylate and 7mL methanol into a 100mL three-necked flask, and slowly add a mixture of 0.04mol p-fluorobenzylamine and 4mL methanol into the three-necked flask while stirring, so that the temperature of the reaction system does not exceed 50°C . After the dropwise addition, heat and reflux for 8 hours. After the reaction is over, recover methanol and unreacted methyl acrylate, and distill under reduced pressure to obtain light yellow oily liquid N,N-bis(β-methyl propionate)-p-fluorobenzyl Amine (2a).

[0059] Add 15mL of anhydrous toluene and 0.122mol of sodium metal to a 250mL dry three-necked flask, stir and heat to reflux, add 0.2mL of anhydrous methanol, and then slowly add 0.04mol of N,N-bis(β-propionate methyl ester)) Mixture of p-fluorobenzylamine (2a) and 20mL of anhydrous tolue...

Embodiment 2

[0063] Example 2: Preparation of 4-p-fluorophenyl-6-p-fluorobenzyl-8-p-fluorobenzylidene-1,2,5,6-tetrahydropyrido[4,3-d]-3,4 - dihydropyrimidine-2-thione (Ib);

[0064] N-p-fluorobenzylpiperidin-4-one (4a) obtained by the preparation method of Example 1, get N-p-fluorobenzylpiperidin-4-one (4a) 0.005mmol and 0.01mol p-fluorobenzaldehyde Mix in a dry 50mL round bottom bottle, add 15mL of absolute ethanol, add 1mL of 10% NaOH while stirring, and a solid precipitates out after about 40min. After the reaction, the solid was washed with ethanol, and recrystallized with ethyl acetate and petroleum ether to obtain N-(4-fluorobenzyl)-3,5-bis(4-fluorobenzylidene)piperidin-4-one (5b).

[0065] Add 10mL of absolute ethanol and 0.005mol of sodium hydroxide to a 100mL dry three-necked flask, stir at room temperature for 5min, then add 0.001mol of N-(4-fluorobenzyl)-3,5-bis(4-fluorobenzylidene base) piperidin-4-one and 0.002 mol of thiourea, set the temperature at 65°C, and used microwav...

Embodiment 3

[0067] Example 3: Preparation of 4-p-tolyl-6-p-fluorobenzyl-8-p-methylbenzylidene-1,2,5,6-tetrahydropyrido[4,3-d]-3,4- Dihydropyrimidine-2-thione (Ic);

[0068] N-p-fluorobenzylpiperidin-4-one (4a) obtained by the preparation method of Example 1, get N-p-fluorobenzylpiperidin-4-one (4a) 0.005mmol and 0.01mol p-toluene Formaldehyde was mixed in a 50mL round bottom bottle, 15mL of absolute ethanol was added, 1mL of 10% NaOH (mass fraction) was added with stirring, and stirred at room temperature for 30min, a yellow solid was precipitated, and the reaction progress was tracked by thin layer chromatography (TLC). After the reaction is over, wash the solid with ethanol, and recrystallize with ethyl acetate and petroleum ether to obtain N-(4-fluorobenzyl)-3,5-bis(4-methylbenzylidene)piperidine-4- Ketone (5c).

[0069] Add 10 mL of absolute ethanol and 0.005 mol of sodium hydroxide to a 100 mL dry three-necked flask, stir at room temperature for 5 min, then add 0.001 mol of N-(4-fl...

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Abstract

The invention provides a sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, a preparation method for the same and application thereof. The sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative is capable of effectively inhibiting cell proliferation of leukaemia K562, ovarian cancer HO-8910 and liver cancer SMMC-7721. The method includes the steps that firstly, substituted amine (a) and acrylic acid methyl ester are manufactured into N by means of Michael addition reaction, secondly, N-bis (beta-acrylic acid methyl ester) substituted amine (b) further gives Dieckmann condensation under the action of sodium alcoholate and hydrolysis decarboxylation reaction under the action of acid to obtain N-substituted piperidine-4-ketone(d), thirdly, the N-substituted piperidine-4-ketone(d) and aromatic aldehyde are reacted by means of bimolecular dehydration so that N-substituted benzyl-3,5-bis benzylidene-piperidine-4-ketone(e) is obtained, and finally, the N-substituted benzyl-3,5-bis benzylidene-piperidine-4-ketone(e) is further reacted so as to obtain the sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative. The method is simple and high in efficiency, and the derivative prepared by the method can have remarkable inhibitory action on above disease cells.

Description

technical field [0001] The invention relates to a derivative capable of inhibiting leukemia, ovarian cancer and liver cancer, in particular to a thiotetrahydropyridodihydropyrimidinone derivative, as well as its preparation and application. Background technique [0002] Among various diseases, cancer poses the greatest threat to human life and is the number one killer of patients. Among all kinds of cancers, leukemia, ovarian cancer and liver cancer are three common malignant tumors with a high incidence rate. Therefore, it is very useful to design and develop drugs that can effectively inhibit the proliferation of leukemia, ovarian cancer and liver cancer cells and make them rapidly apoptotic. significance. [0003] Leukemia is one of the diseases with the highest mortality rate in the world today, which has caused serious harm to human health. The incidence of leukemia in my country ranks sixth among various tumors. Chronic leukemia is a leukemia with clinical onset and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P35/02A61P15/00A61P1/16
Inventor 孙传文丁丽薛思佳
Owner SHANGHAI NORMAL UNIVERSITY
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