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1-methyl-7h-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino) benzyl alkene derivant and preparation thereof

A technology of quinoline triflate and dimethylamino is applied in the field of antitumor drug preparation, can solve the problems of difficult substituents, complicated synthesis steps and the like, and achieves the effects of strong inhibitory effect, simple process and good yield

Inactive Publication Date: 2012-07-18
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Through observation, it is found that the synthesis steps of this type of compound are relatively cumbersome, and it is difficult to introduce substituents on the heterocycle.

Method used

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  • 1-methyl-7h-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino) benzyl alkene derivant and preparation thereof
  • 1-methyl-7h-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino) benzyl alkene derivant and preparation thereof
  • 1-methyl-7h-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino) benzyl alkene derivant and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of 1-methyl-7-(4-dimethylaminobenzene)-7H-inden[1,2-b]quinoline trifluoromethanesulfonate

[0029] (1) Condensation cyclization: 1-indanone (0.46g, 3.5mmol) and anthranilic acid (0.28g, 2mmol) were heated and melted, refluxed at 180°C for 1.5h, and the reaction was terminated. After washing with pyridine and diethyl ether, a yellow solid (0.32 g, 67.6%) was obtained, m.p.360-365.

[0030] (2) Chlorine substitution: the yellow solid obtained in step (1) (0.32 g, 1.35 mmol) was dissolved in phosphorus oxychloride (5 mL), and refluxed at 110° C. for 4 h to complete the reaction. Phosphorus oxychloride was removed under reduced pressure, and saturated NaHCO 3 Adjust to neutral with CH 2 Cl 2 Extracted three times, washed with saturated brine, anhydrous Na 2 SO 4 Dry, filter and evaporate to dryness. Separation and purification by column chromatography, eluting with petroleum ether-ethyl acetate (50:1) gave a white solid (0.30 g, 88.2%), m.p.162-...

Embodiment 2

[0035] Example 2: Preparation of 1,3-dimethyl-7-(4-dimethylaminobenzene)-7H-indene[1,2-b]quinoline trifluoromethanesulfonate

[0036] (1)-(3) method is the same as embodiment one

[0037](4) Methylation reaction: Dissolve 3-methyl-7H-indene[1,2-b]quinoline (0.21g, 0.9mmol) in 5mL of dry CH 2 Cl 2 Medium, N 2 Methyl trifluoromethanesulfonate (0.21 mL, 1.8 mmol) was added under protection, stirred at room temperature for 24 h, and the reaction was tracked by TLC. After the reaction, evaporated to dryness, separated and purified by column chromatography, CH 2 Cl 2 -CH 3 Gradient elution with OH (100:1~50:1) afforded 1,3-dimethyl-7H-indene[1,2-b]quinoline triflate (0.33 g, 96%) as a white solid.

[0038] (5) Coupling reaction: 1,3-dimethyl-7H-inden[1,2-b]quinoline trifluoromethanesulfonate (0.33g, 0.87mmol) and p-dimethylaminobenzaldehyde (0.21 g, 1.30mmol) was refluxed in 50mL glacial acetic acid for 2 days. Distillation under reduced pressure, separation and purification...

Embodiment 3

[0040] Example 3: Preparation of 1-methyl-3-fluoro-7-(4-dimethylaminobenzene)-7H-indene[1,2-b]quinoline trifluoromethanesulfonate

[0041] (1)-(3) method is the same as embodiment one

[0042] (4) Methylation reaction: Dissolve 3-fluoro-7H-inden[1,2-b]quinoline (0.21 g, 0.9 mmol) in 5 mL of dry CH 2 Cl 2 Medium, N 2 Methyl trifluoromethanesulfonate (0.21 mL, 1.8 mmol) was added under protection, stirred at room temperature for 28 h, and the reaction was tracked by TLC. After the reaction, evaporated to dryness, separated and purified by column chromatography, CH 2 Cl 2 -CH 3 OH (100:1~50:1) gradient elution gave white solid 1-methyl-3-fluoro-7H-indene[1,2-b]quinoline trifluoromethanesulfonate (0.31g, 91%) .

[0043] (5) Coupling reaction: 1,3-dimethyl-7H-inden[1,2-b]quinoline trifluoromethanesulfonate (0.31g, 0.82mmol) and p-dimethylaminobenzaldehyde (0.21 g, 1.30mmol) was refluxed in 50mL glacial acetic acid for 2 days. Distillation under reduced pressure, separation...

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Abstract

The invention belongs to the field of antitumor drug preparation, in particular to a 1-methyl-7H-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino)benzyl alkene derivant used as a DNA topoisomerase inhibitor and a preparation method thereof. The preparation method comprises the following steps of: (1) salification reaction: reacting 7H-indene [1, 2-b]quinoline with methyl trifluoromethanesulfonate in the molar ratio of 1 to (2-3) under the protection of nitrogen gas at room temperature with stirring to obtain 7H-indene[1, 2-b]quinolinetrifluoromesylate; (2) coupling reaction: reacting the obtain 7H-indene[1, 2-b]quinolinetrifluoromesylate and 4-dimethylaminobenzaldehyde in the molar ratio of 1.0:(1.4-1.6) in glacial acetic acid in refluxing to prepare the 1-methyl-7H-indene[1, 2-b]quinolinetrifluoromesylate-7-(4-dimethylamino)benzyl alkene derivant. The prepared compound has strong inhibition action on leukemia cells and human laryngeal squamous carcinoma cells; moreover, the preparation method has the advantages of simple process and good yield reaching about 65%.

Description

technical field [0001] The invention belongs to the field of antineoplastic drug preparation, in particular to 1-methyl-7H-indene[1,2-b]quinoline trifluoromethanesulfonate-7-(4- Dimethylamino)benzene derivatives and methods for their preparation. Background technique [0002] Topoisomerase (toposiomerose referred to as Topo) is a basic ribozyme that can catalyze the exchange of DNA topoisomers. It plays an important role in many genetic functions related to DNA, such as DNA replication and transcription, and the separation of homologous chromosomes. According to the different mechanisms of topozyme-induced DNA breakage, it can be divided into two categories: TopoI and TopoII. Currently, TopoI inhibitors are mainly camptothecin and its derivatives (see: US Patent No. 6,242,457). [0003] In 1999 and 2000, the research group of Japanese scientist Katayama reported that pyrazol[1,5-a]indole trifluoromethanesulfonate 4-(4-dimethylamino)benzene derivatives have potent effects o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/18A61K31/473A61P35/00A61P35/02
Inventor 朱永明周舟费香东
Owner SUZHOU UNIV
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