Tricyclic compound as well as preparation method and application thereof

A compound and hydrate technology, applied in the field of medicinal chemistry, can solve problems such as druggability, safety and effectiveness hidden dangers

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

AI Technical Summary

Problems solved by technology

[0008] 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 methanesulfonate may contain impurities from various sources as a raw material drug, and its druggability, safety and the effectiveness of the hidden dangers

Method used

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  • Tricyclic compound as well as preparation method and application thereof
  • Tricyclic compound as well as preparation method and application thereof
  • Tricyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] 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 methanesulfonate

[0061]

[0062] Step 1: Synthesis of 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole

[0063]

[0064] 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 wate...

Embodiment 2

[0080] Example 2N-(5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)-N-(4-(6,7 ,8,9-Tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)acrylamide

[0081]

[0082] Add N to the 250mL three-neck flask 1 -(2-(Dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (1.60g , 3.3mmol, 1.0eq), N,N-dimethylacetamide (16mL), acryloyl chloride (0.90g, 9.9mmol, 3.0eq), N,N-diisopropylethylamine (2.13g, 16.5mmol , 5.0eq), the mixture was stirred at room temperature for 1.5 hours. 50 mL of methanol was added to the reaction mixture to precipitate a solid, which was filtered and dried in vacuo to obtain the title compound, 0.60 g in total, with a yield of 30.0%. 1 HNMR (300MHz, DMSO-d 6 )δ10.03(s,1H),8.59(d,J=5.5Hz,1H),8.19(s,1H),7.91(d,J=8.0Hz,1H),7.45-7.42(m,2H), 7.17(d,J=7.0Hz,1H),7.09-7.06(m,2H),6.77(dd,J 1 =17.0Hz,J 2 =10.3Hz,1H),6.42(dd,J 1 =17.0Hz,J 2 =10.0Hz,1H),6.29(d,J=1...

Embodiment 3

[0083] Example 3N-(4-methoxy-2-(methylamino)-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indole-10- Base) pyrimidin-2-yl) amino) phenyl) acrylamide

[0084]

[0085] Step 1: 2-Methoxy-N 4 -Methyl-5-nitro-N 1 Preparation of -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)phenyl-1,4-diamine

[0086]

[0087] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl ) pyrimidine-2-amine (6.00g, 13.8mmol, 1.0eq), methylamine tetrahydrofuran solution (50mL, 100mmol, 7.2eq) and N,N-dimethylacetamide (60mL) were added to the reaction flask, stirred React overnight at room temperature. Work up the next day yielded 5.50 g of the title compound.

[0088] Step 2: (5-methoxy-2-nitro-4-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidine- Preparation of 2-yl)amino)phenyl)(methyl)carbamate tert-butyl ester

[0089]

[0090] Get the 2-methoxy-N that step 1 makes 4 -Methyl-5-nitro-N 1 -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyr...

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Abstract

The invention belongs to the field of medical chemistry and particularly relates to a tricyclic compound, a preparation method thereof and application thereof as a reference substance in qualitative and / or quantitative analysis of related impurities in the research of the quality of a raw material drug of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl) pyrimidine-2-yl) amino) phenyl)allylamide methanesulfonate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to tricyclic compounds, their preparation methods and their use as reference substances for 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 ) The use of qualitative and / or quantitative analysis of relevant impurities in the quality research of acrylamide methanesulfonate raw materials. 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 survi...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 赵立文符伟吴伟杰刘建设金建淋
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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