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Tetrahydropyridopyran derivatives, preparation methods and applications thereof

A technology of pyran derivatives and tetrahydropyridine, which is applied in the field of pyridopyran derivatives, can solve problems such as threats to women's lives, and achieve remarkable practicability, simple process, and easy production

Inactive Publication Date: 2011-12-21
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the number of deaths due to ovarian cancer ranks first among all types of gynecological tumors, posing a serious threat to women's lives

Method used

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  • Tetrahydropyridopyran derivatives, preparation methods and applications thereof
  • Tetrahydropyridopyran derivatives, preparation methods and applications thereof
  • Tetrahydropyridopyran derivatives, preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Preparation of 6-(4-methylbenzyl)-4-(4-fluorophenyl)-8-(4-fluorobenzylidene)-3-cyano-2-amino-1,2,5 , 6-tetrahydropyrido[4,3-b]pyran (Ia)

[0055] At room temperature, add 0.16mol methyl acrylate and 7mL methanol to a 100mL three-necked flask, slowly add a mixture of 0.04mol p-methylbenzylamine (1a) and 4mL methanol into the three-necked flask while stirring, and the temperature will rise naturally. The drop rate of the mixed solution is controlled within 4mL / min, so that the temperature of the reaction system does not exceed 50°C. After the dropwise addition, the mixture was stirred at room temperature for 20 minutes, and then heated to reflux for 8 hours at a temperature of 63° C., and the reaction progress was tracked by thin layer chromatography (TLC). After the reaction was finished, methanol and unreacted methyl acrylate were recovered and distilled under reduced pressure to obtain light yellow oily liquid N,N-bis(β-methyl propionate)-p-methylbenzylamin...

Embodiment 2

[0059] Example 2: Preparation of 6-(4-methylbenzyl)-4-(2-chlorophenyl)-8-(2-chlorobenzylidene)-3-cyano-2-amino-1,2,5 , 6-tetrahydropyrido[4,3-b]pyran (Ib)

[0060] With the preparation method of Example 1, N-p-methylbenzylpiperidin-4-one (4a) was obtained under the same conditions.

[0061] Add N-p-methylbenzylpiperidin-4-one (4a) (0.005mol) and o-chlorobenzaldehyde (0.01mol) in the round bottom flask of 50ml, 15ml dehydrated alcohol and 10% (mass fraction) sodium hydroxide 1ml. Stir at room temperature for 0.5-2h, a solid precipitated, suction filtered, and washed the product with absolute ethanol to obtain N-p-methylbenzyl-3,5-bis-o-chlorobenzylidene-4-piperidone (5b). Add N-p-methylbenzyl-bis-o-chlorobenzylidene-4-piperidone (5b) (1mmol) to a 25ml round bottom bottle, propanedicyanide (1.5mmol, 99mg) n-butanol (4ml) and heat under reflux After 5 hours, the reflux temperature was 120° C., and the progress of the reaction was tracked by thin layer chromatography (TLC). Af...

Embodiment 3

[0063] Example 3: Preparation of 6-(4-fluorobenzyl)-4-(4-fluorophenyl)-8-(4-fluorobenzylidene)-3-cyano-2-amino-1,2,5 , 6-tetrahydropyrido[4,3-b]pyran (Ic)

[0064] The same preparation method as in Example 1, but p-methylbenzylamine was replaced by p-fluorobenzylamine (1c), and N-p-fluorobenzylpiperidin-4-one (4c) was obtained under the same conditions.

[0065] Add N-p-fluorobenzylpiperidin-4-one (4c) (0.005mol) and p-fluorobenzaldehyde (0.01mol) in the round bottom flask of 50ml, 15ml dehydrated alcohol and 10% (mass fraction) sodium hydroxide 1ml. Stir at room temperature for 0.5-2h, a solid precipitated, suction filtered, and washed the product with absolute ethanol to obtain N-p-fluorobenzyl-3,5-bis-p-fluorobenzylidene-4-piperidone (5c). Add N-p-fluorobenzyl-bis-p-fluorobenzylidene-4-piperidone (5c) (1mmol) to a 25ml round bottom flask, propanedicyanide (1.5mmol, 99mg) n-butanol (4ml) and heat under reflux for 5 hours, the reflux temperature was 120° C., and the progre...

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Abstract

The invention provides a tetrahydropyridine oxapicene derivative and a preparation method thereof. The method comprises the following steps: subjecting substituted amine (a) and methyl acrylate to Michael additive reaction to prepare N,N-bis(beta-methyl propionate) substituted amine (b), subjecting the N,N-bis(beta-methyl propionate) substituted amine (b) to Dieckmann condensation under the action of sodium alkoxide and hydrolysis and decarboxylation under the action of acid to obtain N-substituted piperidine-4-ketone (d), and subjecting two active methylenesand and bimolecular aromatic aldehydes of the N-substituted piperidine-4-ketone (d) to reaction to remove bimolecular water to obtain N-substituted-3,5-2-benzylpiperidine-4-ketone (e); and carrying out reflowing and heating on the N-substituted-3,5-2-benzylpiperidine-4-ketone (e) and malononitrile in normal butanol to obtain a final product shown as a general formula (I). The preparation method is simple in process and convenient for mass production; and the obtained product has a favorable inhibiting effect for the cell proliferation of leukemia K562, oophoroma HO-8910 and liver cancer SMMC-7721.

Description

technical field [0001] The invention relates to a pyridopyran derivative, in particular to a tetrahydropyridopyran derivative capable of effectively inhibiting the proliferation of leukemia K562 cells, ovarian cancer MDR-MB-231 cells and liver cancer SMMC-7721 cells and its preparation method. Background technique [0002] Leukemia, ovarian cancer and liver cancer are three common malignant tumors with a high incidence rate. Therefore, it is of great significance to design and develop drugs that can effectively inhibit the proliferation and rapid apoptosis of leukemia, ovarian cancer and liver cancer cells. [0003] Leukemia is a clonal disease of hematopoietic stem cells. Occurs more frequently in adolescents, and its incidence rate ranks first among adolescent tumors, so the harm to humans is more obvious and prominent. Chronic leukemia is a leukemia with clinical onset and relatively slow development, which is divided into chronic myelogenous leukemia and chronic lympho...

Claims

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Application Information

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IPC IPC(8): C07D491/052A61K31/436A61P35/02A61P35/00
Inventor 孙传文庞春成薛思佳
Owner SHANGHAI NORMAL UNIVERSITY
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