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N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof

A technology of piperidone and double substitution, applied in the field of chemical drugs, can solve the problems of high toxicity and low selectivity, and achieve the effect of effectively inhibiting proliferation

Inactive Publication Date: 2013-01-09
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The common disadvantage of commonly used chemotherapeutic drugs in clinical practice is that their selectivity is not strong, and they have almost the same killing effect on normal cells and tumor cells, and also have a strong killing effect on bone marrow, digestive tract cells and germ cells, so they are more toxic

Method used

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  • N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof
  • N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof
  • N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 N-(4-Methoxybenzyl)-3,5-bis(4-cyanobenzylidene)-4-piperidone (Ia)

[0044] In an ice-water bath at 0°C, add 0.4 mol of methyl acrylate and 7 mL of methanol into a 100 mL three-necked flask. After stirring for 30 minutes, slowly add 0.1 mol of 4-methoxybenzylamine and 10 mL of methanol to the mixed solution to control the drop. Acceleration so that the system temperature does not exceed 50°C (the dropping rate is about 1 drop / sec). After the addition is complete, stir at room temperature for 30 minutes, continue to raise the temperature to 65°C, reflux, and thin layer chromatography (TLC) to track the reaction progress. After reacting for about 8 hours, the reaction was stopped, and methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure.

[0045] A pale yellow oily liquid intermediate (2a) was obtained.

[0046] At room temperature, add 15 mL of anhydrous toluene and 0.1 mol of metallic sodium (cut into blocks) into a 250 mL dry...

Embodiment 2

[0050] Example 2 N-(4-Methoxybenzyl)-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone (Ib)

[0051] (2b) and (3b) are prepared by the same method as (2a) and (3a).

[0052] Add intermediate N-4-methoxybenzyl-4-piperidone (3b) (0.005mol) and 3,4-dichlorobenzaldehyde (0.01mmol) in a 50mL round bottom flask, 15mL of absolute ethanol and 10% (mass fraction) sodium hydroxide 1mL. Stir at room temperature (15~25℃) for 1h, and solids will precipitate out. Filter by suction, then wash the product with absolute ethanol, or recrystallize with ethyl acetate and petroleum ether to obtain the target compound (Ib).

[0053] Yield: 80.2%; yellow solid, mp 131-133°C; 1 H NMR(400MHz, CDCl 3 )δ3.65(s,2H), 3.71(s,3H), 3.85(s,4H), 7.02(d,J=8.7Hz,2H), 7.13(d,J=8.7Hz,2H), 7.24( d,J=8.0Hz,4H),7.36(d,J=8.0Hz,2H),7.71(s,2H); IR(KBr): 2805,2745,1667,1615,1575,1480,1260,1185, 1085,821cm -1 ;Anal.calcd.for C 27 H 21 Cl 4 NO 2 C%60.81,H%3.97,N%2.63;Found:C%60.72H%3.95,N%2.68

Embodiment 3

[0054] Example 3 N-(4-Methoxybenzyl)-3,5-bis(2,4-dichlorobenzylidene)-4-piperidone (Ic)

[0055] Prepare (2c) and (3c) in the same way as (2a) and (3a).

[0056] Add intermediate N-4-methoxybenzyl-4-piperidone (3c) (0.005mol) and 3,4-dichlorobenzaldehyde (0.01mmol) in a 50mL round bottom flask, 15mL of absolute ethanol and 10% (mass fraction) sodium hydroxide 1mL. Stir at room temperature (15~25℃) for 1h, solids will precipitate out, filter with suction, then wash the product with absolute ethanol, or recrystallize with ethyl acetate and petroleum ether to obtain the target compound (Ic).

[0057] Yield: 73.7%; yellow solid, mp 183-185°C; 1 H NMR(400MHz, CDCl 3 )δ3.62(s, 2H), 3.75(s, 3H), 3.82(s, 4H), 7.03(d, J=8.7Hz, 2H), 7.12(d, J=8.7Hz, 2H), 7.22( d,J=8.0Hz,2H),7.28(d,J=8.0Hz,4H),7.73(s,2H);;IR(KBr):2805,2743,1664,1603,1574,1487,1262,1185 ,1094,821cm -1 ;Anal.calcd.for C 27 H 21 Cl 4 NO 2 C%60.81,H%3.97,N%2.63;Found:C%60.72H%3.95,N%2.68

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Abstract

The invention relates to the field of organic synthesis and medicine, and discloses a preparation method for N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and biological activity for efficiently inhibiting cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer. The method includes: starting from various substituted methylamine and methyl acrylate, sequentially going through Michael addition, Dieckmann condensation, acidolysis and decarboxylation to obtain N-substituted methyl-4-piperidone, and subjecting the N-substituted methyl-4-piperidone to aldol reaction with substituted benzaldehyde to obtain a target compound N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone. The target compound can selectively and efficiently inhibit cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer, and activity of inhibiting carcinoma cell line proliferation is obviously higher than conventional chemotherapeutic 5-fluorouracil.

Description

Technical field [0001] The invention belongs to the field of chemical medicine, and specifically relates to N-substituted methyl-3,5-disubstituted benzal-4-piperidone, which can be used as a lead compound for the treatment of leukemia, ovarian cancer, breast cancer, liver cancer and esophageal cancer. . Background technique [0002] Cancer is one of the diseases with the highest mortality rate in the world today. According to the epidemiological statistics released by my country, the incidence of leukemia and primary liver cancer in various regions of our country occupy the sixth and eighth place respectively among various tumors. Leukemia is a type of hematopoietic cell malignant disease that occurs in adolescents. Its incidence ranks first among adolescent tumors. There are currently at least 4 million leukemia patients, with an increase of about 40,000 each year. [0003] Primary liver cancer is one of the most common malignant tumors in the world. More than 50% of liver cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68A61P35/02A61P35/00
Inventor 薛思佳肖笛李静孙传文
Owner SHANGHAI NORMAL UNIVERSITY
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