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Amido pyrimidine compound

A technology of aminopyrimidines and compounds, applied in the field of preparation of 2, inhibitors, can solve the problem of incomplete solution of toxic and side effects, achieve good cytotoxicity, improve solubility, and increase affinity

Active Publication Date: 2020-06-05
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] So far, although irreversible pyrimidine EGFR inhibitors have achieved good clinical effects, it is foreseeable that the problems of patients' acquisition of selective resistance and drug side effects have not been completely resolved, so there is still a need for continuous improvement in this field. Development of new drugs with EGFR inhibitory activity

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] The preparation of embodiment 1 TM-1

[0140]

[0141] Compound 3: Glycine (21.03g, 120mmol) protected by tert-butoxycarbonyl was added to dichloromethane (30ml), and EDCI (25.31g, 132mmol), HOBt (17.82g, 132mmol) and N, N- Dimethylethylenediamine (11.63g, 132mmol), stirred at room temperature for 36h, TLC detected the end of the reaction, removed the solvent under reduced pressure, and redissolved the obtained solid in 120mL mixed solution (DCM:TFA=7:3), stirred at room temperature for reaction After 0.5 h, TLC detected that the reaction was complete, and the solvent was removed by rotary evaporation under reduced pressure, and the product compound 3 was separated by column chromatography with a yield of 76.42%, and HPLC: 99.56%.

[0142]Intermediate III: Add 2,4,6-trichloropyrimidine (Compound 1) (55.03g, 300mmol) into dichloromethane (300ml) and stir until dissolved, cool down to 0-5°C in an ice bath, slowly add 3 -Chloro-4-fluoroaniline (45.71g, 315mmol, compoun...

Embodiment 2

[0146] The preparation of embodiment 2 TM-2

[0147]

[0148] Compound 3: Glycine (21.03g, 120mmol) protected by tert-butoxycarbonyl group was added in dichloromethane (40ml), and EDCI (25.31g, 132mmol), HOBt (17.82g, 132mmol) and cyclohexylamine ( 13.09g, 132mmol), stirred at room temperature for 24h, TLC detected the end of the reaction, removed the solvent under reduced pressure, and redissolved the obtained solid in 150mL mixed solution (DCM:TFA=7:3), stirred at room temperature for 0.5h, and detected the reaction by TLC At the end, the solvent was removed by rotary evaporation under reduced pressure, and the product compound 3 was separated by column chromatography with a yield of 73.62%, HPLC: 99.62%.

[0149] Intermediate III: Add 2,4,6-trichloropyrimidine (compound 1) (55.03g, 300mmol) into ethyl acetate (300ml) and stir until dissolved, cool down to 0-5°C in an ice bath, slowly add 3 -Chloro-4-fluoroaniline (45.72g, 315mmol, compound 2), the ice bath was removed a...

Embodiment 3

[0153] The preparation of embodiment 3 TM-3

[0154]

[0155] Compound 3: Glycine (21.03g, 120mmol) protected by tert-butoxycarbonyl was added to dichloromethane (30ml), and EDCI (25.31g, 132mmol), HOBt (17.82g, 132mmol) and aniline (12.29g) were added successively , 132mmol), stirred at room temperature for 24h, TLC detected the end of the reaction, removed the solvent under reduced pressure, and the resulting solid was redissolved in 120mL mixed solution (DCM:TFA=7:3), stirred at room temperature for 0.5h, and TLC detected the end of the reaction. The solvent was removed by rotary evaporation under reduced pressure, and the product compound 3 was separated by column chromatography with a yield of 75.61%, HPLC: 99.71%.

[0156] Intermediate III: Add 2,4,6-trichloropyrimidine (compound 1) (55.03g, 300mmol) into acetone (300ml) and stir until dissolved, cool down to 0-5°C in an ice bath, and slowly add 3-chloropyrimidine dropwise -4-Fluoroaniline (45.72g, 315mmol, compound ...

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Abstract

The invention provides an amido pyrimidine compound with a novel structure as shown in a formula (I) and a preparation method and application of the amido pyrimidine compound. The amido pyrimidine compound is a compound shown as the formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and the like. The amido pyrimidine compound provided bythe invention has a relatively good proliferation inhibition effect on various cancer cells; according to the present invention, the compound has characteristics of low tumor cell inhibition concentration, significantly-improved compound activity, good tumor cell selectivity and good solubility, and is expected to be a specific drug for treatment of malignant tumor cell abnormal proliferation diseases caused by EGFR mutation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a 2,4,6-triaminopyrimidine EGFR inhibitor, a preparation method and application of the inhibitor. Background technique [0002] Protein tyrosine kinases, a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues located on protein substrates, play a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases and affect signaling through this process to regulate cell growth. However, under certain conditions, these receptors are either mutated or overexpressed, becoming abnormal, causing cells to multiply uncontrollably, leading to tumor growth and ultimately the well-known disease - cancer. Growth factor receptor protein tyrosine kinase inhibitors play a role in the treatment of cancer by inhibiting the above phosphorylation process. [0003] The epidermal growth factor receptor EGFR is also ca...

Claims

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Application Information

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IPC IPC(8): C07D239/50
CPCC07D239/50
Inventor 张贵民唐贞波白文钦杨伟河马永杰
Owner LUNAN PHARMA GROUP CORPORATION
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