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Synthesis and anti-tumor activity of camphoryl pyrimidines

A technology based on compound and pyrimidine, which is applied in the synthesis of camphor-based pyrimidine compounds and its anti-tumor activity, can solve the problems of high toxicity and side effects, achieve high selectivity and yield, high solvent recovery rate, and simple synthesis process Effect

Inactive Publication Date: 2019-12-10
NANJING FORESTRY UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, with the in-depth study of pyrimidine compounds, a large number of pyrimidine anti-tumor drugs have been reported, but due to the high toxicity and side effects, only a small amount can enter clinical trials

Method used

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  • Synthesis and anti-tumor activity of camphoryl pyrimidines
  • Synthesis and anti-tumor activity of camphoryl pyrimidines
  • Synthesis and anti-tumor activity of camphoryl pyrimidines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 4-(2'-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanoquinazolin-2-amine (compound 1 )

[0030]

[0031] In a 50ml three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add guanidine hydrochloride (8mmol), tert-butanol (35mL) and potassium tert-butoxide (12mmol) successively, and stir to make guanidine hydrochloride and potassium tert-butoxide Dissolve, add 3-(2-fluorobenzylidene) camphor (2 mmol), and heat to reflux for 10 h (TLC tracking detection). After the reaction, the reaction solution was concentrated to remove tert-butanol, added ethyl acetate, washed with distilled water and saturated brine to neutrality, and then washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to obtain a brown crude product, which is recrystallized from methanol to obtain a white solid powder. Yield 92.6%; m.p.166.2~166.4℃; 1 H NMR (400MHz, CDCl 3 )δ: 7.57(s, 1H), 7.40(s, 1H), 7.13(s, 2H), 5.39(s, 2H), 2.79(s, 1H), 2.28(s, ...

Embodiment 2

[0033] 4-(3'-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanoquinazolin-2-amine (compound 2 )

[0034]

[0035] The preparation method is the same as in Example 1. Substitute 2-fluorobenzaldehyde with 3-fluorobenzaldehyde to obtain a white solid powder. Yield 88.9%; m.p.155.4~155.9℃; 1 H NMR (400MHz, CDCl 3 )δ: 7.49-7.55 (m, 2H), 7.39-7.44 (m, 1H), 7.09-7.14 (m, 1H), 5.31 (s, 2H), 3.06 (d, J=4Hz, 1H), 2.18- 2.23 (m, 1H), 1.86-1.96 (m, 1H), 1.32-1.37 (m, 2H), 1.25 (s, 3H), 0.99 (s, 3H), 0.63 (s, 3H); 13 C NMR (100MHz, CDCl 3 )δ: 182.24, 164.11, 161.75, 154.70, 140.38, 129.98, 125.48, 123.96, 116.18, 115.33, 55.96, 54.25, 49.65, 31.76, 25.95, 19.96, 18.98, 10.03; + ): m / z calculated for C 18 h 20 FN 3 [M+H] + 298.1720, found 298.1717.

Embodiment 3

[0037] 4-(4'-fluorophenyl)-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanoquinazolin-2-amine (compound 3 )

[0038]

[0039] The preparation method is the same as in Example 1. Substitute 2-fluorobenzaldehyde with 4-fluorobenzaldehyde to obtain a white solid powder. Yield 91.5%; m.p.197.0~197.9℃; 1 H NMR (400MHz, CDCl 3)δ: 7.75-7.79(m, 2H), 7.14(t, J=8Hz, 2H), 5.27(s, 2H), 3.03(d, J=3.9Hz, 1H), 2.16-2.22(m, 1H) , 1.86-1.95(m, 1H), 1.32-1.36(m, 2H), 1.25(s, 3H), 0.99(s, 3H), 0.63(s, 3H); 13 C NMR (100MHz, CDCl 3 )δ: 181.98, 164.66, 161.74, 155.07, 134.17, 130.24, 125.17, 115.32, 55.97, 54.21, 49.70, 31.76, 25.97, 19.95, 19.01, 10.03; HR-MS (ESI + ): m / z calculated for C 18 h 20 FN 3 [M+H] + 298.1720, found 298.1717.

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Abstract

The invention discloses camphoryl pyrimidines, and a preparation method and an anti-tumor activity study thereof. With camphor as a raw material and under an alkaline catalysis condition, a series ofalpha,beta-unsaturated ketones are obtained through aldol condensation reaction of camphor with different aromatic aldehydes respectively, a series of camphoryl pyrimidines are obtained through annulation reaction of alpha,beta-unsaturated ketones with guanidine hydrochloride through catalysis of potassium tert-butoxide, and the anti-tumor activity of the synthesized camphoryl pyrimidines is studied. Experiments show that the camphoryl pyrimidines have good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), have less toxicity on normal cell human gastric mucosa cells (GES-1), and have potential anti-tumor application value.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and drug synthesis, and relates to the synthesis of camphor-based pyrimidine compounds and their antitumor activity. Background technique [0002] Tumor has always been the number one killer that endangers human health, so anti-tumor drugs have always been the focus of new drug research and development. Due to the diversity of natural product structures and a wide range of physiological activities, obtaining anticancer drugs from natural products has become a hot field for the development of anticancer drugs at home and abroad. Camphor is a natural product with a high yield in my country. Its chemical name is 2-camphorone. Through rearrangement reactions, functional effects on C and breakage of C-C bonds, camphor can be used as an ideal raw material for optically active compounds. It is used in the field of chiral catalysis There are many studies, but relatively few studies have introduc...

Claims

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Application Information

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IPC IPC(8): C07D239/70A61P35/00
CPCC07D239/70A61P35/00
Inventor 王石发张燕徐徐王忠龙谷文杨益琴徐海军匡红波周新成
Owner NANJING FORESTRY UNIV
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