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Preparation method of tricyclic EGFR kinase inhibitor

A solvate and organic solvent technology, applied in the field of medicinal chemistry, to achieve high yield and purity, easy operation, and easy purification

Active Publication Date: 2019-05-03
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no disclosure of a preparation method suitable for industrial production of the compound of formula I or its pharmaceutically acceptable salt, crystal, hydrate or solvate at present in the art. The preparation method of crystallization, hydrate or solvate is researched to obtain the preparation formula I compound or its pharmaceutically acceptable salt, crystallization, hydration method of substance or solvate

Method used

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  • Preparation method of tricyclic EGFR kinase inhibitor
  • Preparation method of tricyclic EGFR kinase inhibitor
  • Preparation method of tricyclic EGFR kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydro Preparation of pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0042]

[0043] Step 1: Synthesis of 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole

[0044]

[0045] In a 100L vertical jacketed glass reactor, add ethylene glycol dimethyl ether (39.15kg) and 2,4-dichloropyrimidine (3.915kg), cool the solid-liquid mixture to below 10°C, and add anhydrous Aluminum chloride (3.855kg), the rate of addition is controlled, and the temperature is not higher than 30°C. After the addition is complete, stir at 25±5°C for 30 minutes, then add 6,7,8,9-tetrahydropyrido[1,2-a]indole (4.500kg), heat up, and react 3 at 60±5°C After 1 hour, the HPLC monitors that the content of 6,7,8,9-tetrahydropyrido[1,2-a]indole does not exceed 1.0%, and the reaction is determined to be complete. Cool the reaction solution below 25°C, add purified water (90.0kg), stir,...

Embodiment 2

[0061] Example 2: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9- Synthesis of Tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0062]

[0063] The preparation method was the same as the preparation method in Step 5 of Example 1, except that N,N-dimethylacetamide was replaced by N,N-dimethylformamide to obtain the title compound with a purity of 69%.

[0064] N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7, 8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide has higher yield and purity, mild reaction conditions, and purification Easy, stable process, easy to operate, environmentally friendly, and able to meet industrial-scale production and application.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of a tricyclic EGFR kinase inhibitor, and specifically relates to a preparation method of a compoundof formula i or a pharmaceutically acceptable salt, a crystal, a hydrate or a solvate thereof. The preparation method of the compound of formula i or the pharmaceutically acceptable salt, the crystal, the hydrate or the solvate thereof has relatively high yield and purity, the reaction conditions are mild, the purification is easy, the process is stable, the operation is easy, the environment friendly effect is achieved, and the industrial scale production and application can be met.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7 ,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide or its pharmaceutically acceptable salt, crystal, hydrate or Preparation of solvates. Background technique [0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase member of the erbB receptor family. Homodimerization and / or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain, stimulating many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many cancers, such as lung, head and neck, and breast cancers, among others. Small-molecule EGFR tyrosine kinase inhibi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
Inventor 赵立文符伟吴伟杰刘建设金建淋
Owner NANJING SANHOME PHARMACEUTICAL CO LTD