1-methyl-5h-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative and preparation method thereof

A technology of pyridine trifluoromethanesulfonate and dimethylamino, which is applied in the field of preparation of antitumor drugs, can solve the problems of cumbersome synthesis steps and difficult substituents, and achieve the effects of simple process, strong inhibitory effect and good yield

Inactive Publication Date: 2012-06-06
SUZHOU UNIV
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  • Abstract
  • Description
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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-5h-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative and preparation method thereof
  • 1-methyl-5h-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative and preparation method thereof
  • 1-methyl-5h-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative and preparation method thereof

Examples

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Embodiment 1

[0028] Example 1: Preparation of 1-methyl-5-(4-dimethylaminobenzene)-5H-inden[1,2-b]pyridine trifluoromethanesulfonate

[0029] (1) Preparation of enamine: Dissolve 1-indanone (5.28g, 0.04mol) in 25mL benzene, add morpholine (9mL, 0.1mol) and catalytic amount of toluene-4-sulfonic acid, stir and reflux until oil-water separation The instrument no longer observes the formation of water. Distilled under reduced pressure to obtain an amber oily product;

[0030] (2) Condensation and cyclization: 3-bromopropylamine hydrobromide (2.19g, 0.01mol) was dissolved in 10mL of dry DMF, and the oil obtained in step (1) (2.21g, 0.011mol) was added, and dissolved in 100- 110°C, stirred and refluxed for 4h. After the reaction, the reaction solution was poured into 5% hydrochloric acid solution (15mL), and extracted with ether to remove non-alkaline substances; an excess of 50% sodium hydroxide solution was added to the aqueous layer, extracted three times with ether, and the ether layer was...

Embodiment 2

[0035] Example 2: Preparation of 1-methyl-8-fluoro-5-(4-dimethylaminobenzene)-5H-indene[1,2-b]pyridine trifluoromethanesulfonate

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

[0037] (4) Methylation reaction: Dissolve 8-fluoro-5H-inden[1,2-b]pyridine (0.16 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 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) gave white solid 1-methyl-8-fluoro-5H-indene[1,2-b]pyridine trifluoromethanesulfonate (0.26g, 91%);

[0038] (5) Coupling reaction: 1-methyl-8-fluoro-5H-inden[1,2-b]pyridine trifluoromethanesulfonate (0.26g, 0.82mmol) and p-dimethylaminobenzaldehyde (0.18 g, 1.21mmol) was refluxed in 50mL glacial acetic acid for 2 days. Distillation under reduced pressure, separati...

Embodiment 3

[0040] Example 3: Preparation of 1,8-dimethyl-5-(4-dimethylaminobenzene)-5H-indene[1,2-b]pyridine trifluoromethanesulfonate

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

[0042] (4) Methylation reaction: Dissolve 8-methyl-5H-inden[1,2-b]pyridine (0.16 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 20 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 1,8-dimethyl-5H-indene[1,2-b]pyridine trifluoromethanesulfonate (0.29g, 97%);

[0043] (5) Coupling reaction: 1,8-dimethyl-5H-inden[1,2-b]pyridine trifluoromethanesulfonate (0.29g, 0.88mmol) and p-dimethylaminobenzaldehyde (0.18g , 1.21mmol) was refluxed in 50mL glacial acetic acid for 2 days. Distillation under reduced pressure, separation and purificatio...

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Abstract

The invention belongs to the field of anti-tumor medicine preparation and in particularly relates to a 1-methyl-5H-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative used as a DNA topoisomerase inhibitor and a preparation method thereof. The preparation method comprises the following steps of: (1) salifying reaction: stirring and reacting 5H-indene (1,2-b) pyridine and trifluoromethanesulfonic methyl ester in the molar ratio of 1:2-3 under the nitrogen protection at room temperature to obtain 1-methyl-5H-indene (1,2-b) pyridine trifluoromethanesulfonic salt; and (2) coupling reaction: distilling the 1-methyl-5H-indene (1,2-b) pyridine trifluoromethanesulfonic salt obtained in the step (1) with 4-dimethylaminobenzaldehyde in the molar ratio of 1.0:1.4-1.6 in glacial acetic acid to obtain the 1-methyl-5H-indene (1,2-b) pyridine trifluoromethanesulfonic salt-5-(4-dimethylamino group) benzylidene derivative. The obtained compound has strong function for inhibiting leukemia cell and human laryngeal squamous carcinoma. Besides, the preparation method has simple process and good productivity as high as about 65%.

Description

technical field [0001] The invention belongs to the field of preparation of antineoplastic drugs, in particular to 1-methyl-5H-inden[1,2-b]pyridine trifluoromethanesulfonate-5-(4-di Methylamino)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 respectively reported that pyrazol[1,5-a]indole trifluoromethanesulfonate-4-(4-dimethylamino)benzene derivatives have p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/16A61K31/435A61P35/00A61P35/02
Inventor 朱永明李雯闻娣娣
Owner SUZHOU UNIV
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