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Preparation method for antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor

A technology of reagents and general formulas, applied in the field of drug synthesis, can solve problems such as unsuitable for large-scale production, increasing environmental pressure, and high irritation

Active Publication Date: 2019-05-17
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This patent uses 3-(2-chloropyrimidin-4-yl)-1-cyclopropyl-1H-indole as raw material to prepare N-(5- ((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl) acryloylamide, but because raw materials are difficult to purchase on a large scale, it is not suitable for large-scale industrial production
[0012] and the journal J.Org.Lett.2008,10,1653-1655 announced a cyclopropyl boronic acid and 1H-indole derivatives as raw materials to prepare 1- Cyclopropyl-1H-indole derivatives, but this method has the following defects: the amount of cyclopropylboronic acid is large, and the price of cyclopropylboronic acid is relatively expensive, which greatly increases the reaction cost and is not suitable for large-scale production; the reaction uses Copper acetate and DMAP are raw materials, but DMAP has high toxicity and high irritation, is not suitable for large-scale use and increases environmental protection pressure; This reaction uses toluene as solvent, and toluene also has strong irritation; High temperature, harsh reaction conditions

Method used

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  • Preparation method for antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor
  • Preparation method for antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor
  • Preparation method for antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl Preparation of base) amino)-4-methoxyphenyl)acrylamide mesylate

[0120]

[0121] The first step: the preparation of 3-(2-chloropyrimidin-4-yl)-1H-indole

[0122]

[0123] Add indole (236.0 g, 2.02 mol), tetrahydrofuran (1200 mL) into the reaction flask. Cool to 0°C, under nitrogen protection, slowly add methylmagnesium bromide (672 mL, 3 mol / L 2-methyltetrahydrofuran solution) dropwise into the system. After the dropwise addition was complete, stir for 1 hour. Add 2,4-dichloropyrimidine (120.0 g, 0.81 mol) and stir for 1 hour. Heat to an internal temperature of 70°C, stir the reaction at this temperature for 5h, stop heating, and cool to room temperature. Ethyl acetate (600 mL) was added to the reaction flask, followed by saturated aqueous ammonium chloride (1200 mL). Stir to separate the layers and save the organic phase. The aqueous phase was extracted with ethy...

Embodiment 2

[0149] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-((2- Preparation of (dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

[0150]

[0151] The first step: 4-(1-cyclopropyl-1H-indol-3-yl)-N-(2-(difluoromethoxy)-4-fluoro-5-nitrophenyl)pyrimidine-2 - Preparation of amines

[0152]

[0153] 3-(2-Chloropyrimidin-4-yl)-1-cyclopropyl-1H-indole (80 mg, 0.29 mmol) and 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (64mg, 0.29mmol) was dissolved in 2-pentanol, heated to microwave reaction for 1 hour, cooled to room temperature, evaporated to remove the solvent, and the residue was separated and purified by preparative thin layer chromatography to obtain 4-(1-cyclopropyl-1H -indol-3-yl)-N-(2-(difluoromethoxy)-4-fluoro-5-nitrophenyl)pyrimidin-2-amine (76 mg).

[0154] MS m / z(ESI):456.1[M+H] + .

[0155] The second step: N1-(4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)-2-(difluoromethoxy)-N4-(2-(dimethyl Preparation of amino)ethyl)-N4-met...

Embodiment 3

[0170] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl Preparation of (yl)amino)-4-(trifluoromethoxy)phenyl)acryloylamide

[0171]

[0172] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl Base) amino) -4- (trifluoromethoxy) phenyl) acryloylamide The preparation method is similar to Example 1.

[0173] 1 H NMR (400MHz, CD 3 OD)δ9.56(s,1H),8.89(s,1H),8.56(m,1H),8.08(d,1H),7.71(d,1H),7.50(d,1H),7.32(m, 3H),6.96(m,1H),6.79-6.43(m,2H),6.09(dd,1H),5.85(d,1H),3.62(m,2H),2.75(m,3H),2.40-2.50 (m,3H),2.94(s,6H),1.24(m,2H),1.14(m,2H);

[0174] MS m / z(ESI):580.6[M+H] + .

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Abstract

The invention relates to a preparation method for an antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor. Specifically, the invention relates to a preparation method for a 4-(1-cyclopropyl-1H-indole-3-yl)-N-phenylpyrimidine-2-amine derivative of a compound structure shown in a general formula (IV). According to the method, defects in the prior art are overcome; cost is greatly shortened; an obtained product has high purity, high yield and high technical maneuverability; and technical safety is greatly improved. Therefore, the preparation method disclosed by the invention and the application of the preparation method are suitable for industrial application.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method and application of a 4-(1-cyclopropyl-1H-indol-3-yl)-N-phenylpyrimidin-2-amine derivative. Background technique [0002] EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane protein tyrosine kinase erbB receptor family. EGFR can form homodimers on the cell membrane by binding to its ligands, such as epidermal growth factor (EGF), or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4) . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in cells. These intracellular signaling pathways play important roles in cell proliferation, survival and anti-apoptosis. Dysregulation of EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can ...

Claims

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Application Information

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IPC IPC(8): C07D403/04
CPCC07D403/04Y02P20/55
Inventor 赵军军孙长安蓝月徐丹丹
Owner JIANGSU HANSOH PHARMA CO LTD
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