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A class of 2,3-lactam ring-fused quinazolin-4(3h)-one derivatives and its preparation method and application

A technology of ring-fused quinazoline and lactam, which is applied in the field of pharmaceutical preparation, can solve the problem of not many researches on combining and combining, and achieves the effects of simple post-processing, easy operation and mild conditions.

Active Publication Date: 2018-12-07
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Most of the above-mentioned fused ring structures are merging a heterocycle on the A ring of quinazoline, and some research progress has been made, but there are not many studies on the merging of its B ring.

Method used

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  • A class of 2,3-lactam ring-fused quinazolin-4(3h)-one derivatives and its preparation method and application
  • A class of 2,3-lactam ring-fused quinazolin-4(3h)-one derivatives and its preparation method and application
  • A class of 2,3-lactam ring-fused quinazolin-4(3h)-one derivatives and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: Synthesis of 4-oxo-3,4-dihydroquinazoline-2-carboxylic acid ethyl ester (8)

[0064] Add anthranilamide (6, 6.8g, 50mmol), diethyl oxalate (7, 50mL, 367mmol) and a magneton into a 250ml three-necked flask, heat and stir, and the temperature is 140°C at this time, by clarification The light yellow color of the reaction solution changed to turbid orange red, and reflux began at 150° C. after one hour, and turned yellowish white after five hours. After 48 hours, the product showed no fluorescence, indicating that the reaction was complete. After cooling to room temperature, a solid precipitated out. Filter with suction and wash with absolute ethanol to obtain a filter cake. The obtained filter cake was recrystallized with absolute ethanol, and the obtained product was dried under vacuum to obtain the desired intermediate 8 (4.928 g, 44.8%) as fine white needle-like crystals, m.p.185.8-187.4°C.

Embodiment 2

[0065] Embodiment 2: Synthesis of 4-oxo-3,4-dihydroquinazoline-2-carboxylic acid ethyl ester (8)

[0066] Diethyl oxalate (7, 50 mL, 0.366 mol) was slowly and carefully added to melted 2-aminobenzamide (6, 6.8 g, 0.05 mol) in portions. The reaction mixture was stirred and heated to reflux for 48 hours, followed by thin layer chromatography (TLC) monitoring (developing solvent: DCM-Et 2O, v:v=1:1) reaction process. After confirming that the reaction was complete, the reaction liquid was cooled to room temperature, and excess diethyl oxalate was distilled off under reduced pressure. The obtained solid was washed with cold ethanol (100 mL), and the filter cake obtained after suction filtration was resuspended in cold diethyl ether (50 mL), stirred for 0.5 hours, and filtered to obtain the desired intermediate (8, 8.6 g, 78.9%) as fine white Needle-like crystals, m.p.190–191°C.

Embodiment 3

[0067] Example 3: Synthesis of 4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester (8)

[0068] Set up the reflux device, add anthranilamide (6, 6.8g, 50mmol) and diethyl oxalate (7, 50mL, 367mmol) and magneton into a 250mL three-necked bottle, heat and stir, and the temperature is 140 °C, from clear light yellow to turbid orange red, reflux at 150 °C after one hour, and turn into yellowish white after 5 hours, TLC monitoring after 48 hours of reaction, the product has no fluorescence or fluorescent spots, indicating that the reaction is complete . After cooling to room temperature, a solid precipitated out. The filter cake was obtained by suction filtration and washed with absolute ethanol. Recrystallized from absolute ethanol and dried in vacuo to obtain the desired intermediate product (8, 5.84g, 53.1%), m.p.186-187°C.

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Abstract

The invention discloses a class of 2,3-lactam ring fused quinazoline-4(3H)-one derivatives, a preparation method and applications thereof. According to the present invention, a series of novel-structure simplified tricyclic fused quinazoline derivatives are designed and synthesized by using the fused quinazoline ring contained in a natural product luotonin A as a template, and an anti-liver-cancer-cell activity testing experiment is performed on the derivatives, such that a certain research direction is provided for the structural transformation of the luotonin and the camptothecin, and the novel guide structure is provided for the further discovery of the antitumor drugs. According to the present invention, the results of the multiple tests verify that the method relates to the continuous 4-5 step traditional chemical reaction (intermolecular cyclization, alkylation, amination, intramolecular cyclization and substitution), it is proved that the yield of the final product is easily improved by setting the reaction sequence from a plurality of the fields, the whole synthesis route for the synthesis of the compounds is firstly and publicly reported, and the reference method can be provided for the synthesis of a large number of the derivatives and the structural transformation.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation and relates to the research and development and preparation of medicinal chemistry-based lead compounds, in particular to a class of 2,3-lactam ring-fused quinazolin-4(3H)-one derivatives and a preparation method and application thereof. Background technique [0002] As a dominant framework of medicinal chemistry, quinazoline constitutes many compounds with a wide range of biological activities, such as anti-inflammatory, antibacterial, anti-tuberculosis, anti-diabetic, anti-HIV and anti-tumor activities. Many quinazoline compounds have obvious inhibitory activity on various anti-tumor drug targets, such as EGFR, PARP, MPS1, JAK2, CHK-2 and Pin1. The newly listed antineoplastic drugs Gefitinib (Gefitinib), Erlotinib (Erlotinib) and Lapatinib (Lapatinib) as tyrosine kinase inhibitors all contain the heterocyclic structural characteristics of quinazoline, and the structure is as follows...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D239/90A61P35/00
CPCC07D239/90C07D487/04
Inventor 孟歌葛维娟康玉明谢紫轩陈萍孙靓祁艺金犇魏兰兰
Owner XI AN JIAOTONG UNIV
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