Quinazoline derivative, preparation method, intermediate, composition and application

A technology of quinazoline and derivatives, applied in the field of quinazoline derivatives, can solve problems such as reversible inhibitor resistance

Active Publication Date: 2013-01-30
SHANGAI PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, Gefitinib and Erlotinib, which are already on the market, are reversible inh...

Method used

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  • Quinazoline derivative, preparation method, intermediate, composition and application
  • Quinazoline derivative, preparation method, intermediate, composition and application
  • Quinazoline derivative, preparation method, intermediate, composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide Preparation of (Compound 1)

[0198]

[0199] Step 1 Preparation of 4-(3-chloro-4-fluorophenylamino)-6-(2-fluoro-2-diethoxyphosphonoacetyl)amino-7-methoxyquinazoline

[0200] Raw material: 6-amino-4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazoline was prepared according to the method in J.Med.Chem.2009, 52, 6880-6888.

[0201]Raw material: 2-fluoro-2-diethoxyphosphoryl acetyl chloride was prepared according to the method in the literature Heterocycles, 2004, 63, 699-706.

[0202] 6-Amino-4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazoline (1 eq.) and triethylamine (1.5 eq.) were dissolved in DMF (10 ml), the The solution was stirred at 0 °C for 30 min. A solution of 2-fluoro-2-diethoxyphosphorylacetyl chloride (1.5eq.) in DMF (5ml) was slowly added dropwise to the above solution, and the reaction was stirred overnight at room temperature. After the reaction,...

Embodiment 2

[0211] (Z)-N-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobutyl- 2-enamide and (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)- Preparation of 2-fluorobut-2-enamide

[0212]

[0213] The mixture of cis and trans isomers obtained in Example 1 was separated by using Gilson 215 semi-preparative chromatograph (322 type pump, 156 type UV detector).

[0214] Chromatographic column: Phenomenon Gimini 30×250mm, 10μm

[0215] Detection wavelength: 254nm

[0216] Column temperature: room temperature

[0217] Sample processing method: the sample (mixture of cis and trans isomers) was dissolved in methanol and obtained by filtration. The concentration is 22mg / ml, and the injection volume of each needle is 800μL.

[0218] Mobile phase: water: acetonitrile (with 0.05% ammonia added) = 49:51

[0219]

[0220] The fraction with a retention time of 14.5 min was collected to obtain the (Z)-type isomer (comp...

Embodiment 3

[0227] According to the same method as in Example 1, using different raw materials, the following compounds were prepared, all of which were mixtures of cis and trans isomers.

[0228] Compound 3-1: N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxy)ethoxyquinazolin-6-yl)-4-(dimethyl Amino)-2-fluorobut-2-enamide

[0229]

[0230] The raw material 6-amino-4-(3-chloro-4-fluorophenylamino)-7-(2-methoxy)ethoxyquinazoline was prepared according to the method of document WO2008 / 33747; other raw materials were prepared as in Example 1 .

[0231] MS (ESI + ): m / z=492, 493, 494 [M+H] +

[0232] Rf value: 0.38 (silica gel, ethyl acetate / methanol=9:1)

[0233] Compound 3-2: N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobutyl -2-enamide

[0234]

[0235] Raw material 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazoline according to 6-amino-4-(3-chloro-4-fluorophenyl in document WO2008 / 33747 Amino)-7-(2-methoxy)ethoxyquinazoline ...

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Abstract

The invention discloses a quinazoline derivative and a pharmaceutically acceptable salt thereof showed in a formula I, or their enantiomer, diastereoisomer, tautomer, racemate, solvate, metabolic precursor or prodrug. The invention also discloses a preparation method, an intermediate, a composition and an application. The quinazoline derivative has good antineoplastic activity.

Description

technical field [0001] The present invention specifically relates to a quinazoline derivative, its preparation method, its intermediate, its pharmaceutical composition and its application. Background technique [0002] Protein kinases play an important role in cell signaling. It can transfer phosphate groups from ATP to specific amino acid residues in functional proteins, triggering a series of biochemical reactions. According to the type of amino acid used as a substrate in the phosphorylation process, protein kinases can be divided into serine-threonine kinases (STKs) and tyrosine kinases (PTKs). Among them, PTKs can be divided into three categories: ① receptor tyrosine kinases (receptor protein tyrosine kinases, RPTKs), which are single transmembrane proteins, and more than 50 species have been found in vertebrates; ② cytoplasmic tyrosine kinases, such as Src family, Tec family, JAK family, etc.; ③nuclear tyrosine kinases such as Abl and Wee. [0003] The extracellular...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D405/12C07D403/12C07D401/12C07D413/12C07F9/6512C07F9/6558A61K31/517A61K31/5377A61P35/00
CPCC07D403/12C07F9/6512A61K31/517C07D405/12C07D401/12A61K31/5377C07D239/94C07D413/12C07F9/6558A61P35/00A61P43/00
Inventor 夏广新沈竞康俞永平陈文腾张春春郝宇张晶李柏俊刘学军
Owner SHANGAI PHARMA GRP CO LTD
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