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A kind of preparation method of pyridone derivatives and its intermediate

A pyridyl compound technology, applied in the field of preparation of cancer drugs, can solve the unfavorable industrial expansion of production, long reaction time, low yield and other problems

Active Publication Date: 2021-07-27
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The method finally obtains the target product through preparation and separation purification, and the yield is 30.3%. This method has many reaction steps, long reaction time, high temperature reaction (reaction temperature of the seventh step is 230° C.), low yield, etc. Problems, not conducive to industrial expansion of production

Method used

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  • A kind of preparation method of pyridone derivatives and its intermediate
  • A kind of preparation method of pyridone derivatives and its intermediate
  • A kind of preparation method of pyridone derivatives and its intermediate

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specific Embodiment approach

[0162] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0163] The experimental methods not indicating specific conditions in the examples of the present invention are generally in accordance with conventional conditions, or in accordance with the conditions suggested by raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.

Embodiment 1

[0168] Example 1, 2-(2-fluoro-4-iodoanilino)-1-methyl-4-(6-methylpyridin-3-yloxy)-6-carbonyl-1,6-dihydropyridine - Preparation of 3-formamide (compound 31 or IIA)

[0169]

[0170] first step

[0171] 2-amino-4-hydroxy-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carbonitrile (1-1)

[0172] Dimethyl malonate (39.6g, 0.3mol), malononitrile (19.8g, 0.3mol) and tetrahydrofuran (200ml) were added to the reaction flask, and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU, 91.34g, 0.6mol), the dropwise addition was completed in 1 hour, stirred at room temperature for 18h, added dropwise with 30% methylamine aqueous solution (200ml), at room temperature Stir for 24h. Add sodium hydroxide solution (10N, 45ml) dropwise, stir at room temperature, react for 5h, add acetone and stir for 30min to filter under ice bath, collect the filter cake, dry under reduced pressure to obtain the title product (40g, light yellow solid), yield 80.8 %.

[0173] MS m / z(ESI): 166.2[M+1]

[0174] second step...

Embodiment 2

[0199] Example 2, 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-carbonyl-1, Preparation of 6-dihydropyridine-3-carboxamide p-toluenesulfonate

[0200]

[0201] (1) Preparation of crude product

[0202] Drop into 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-carbonyl-1 in the reaction bottle, 6-dihydropyridine-3-carboxamide (43g, 0.09mol), p-toluenesulfonic acid (19.0g, 0.10mol) and isopropanol (1.0kg), reflux for 2-2.5h. Stop heating, continue stirring for 12-14 h, stop the reaction, filter, wash the filter cake with isopropanol, and dry under reduced pressure to obtain the product (56.2 g, yield 97.0%, purity not less than 97% by HPLC).

[0203] (2) Purification of the product

[0204] Drop into 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-carbonyl-1 in the reaction bottle, 6-dihydropyridine-3-carboxamide p-toluenesulfonate crude product (52.9g, 0.08mol), acetone (715g), purified water...

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Abstract

The invention relates to a preparation method of pyridone derivatives and an intermediate thereof. Specifically, the present invention relates to a preparation method for preparing pyridone derivatives represented by formula (II) and pharmaceutically acceptable salts thereof from compounds represented by formula (6), intermediates in the preparation process and preparation methods thereof.

Description

technical field [0001] The present invention relates to a preparation method of a pyridone derivative, a pharmaceutically acceptable salt thereof, an intermediate in the preparation process and a preparation method thereof, the pyridone derivative, a pharmaceutically acceptable salt thereof and a medicine containing the derivative The use of the composition as a MEK inhibitor in the preparation of medicines for treating cancer. Background technique [0002] Ser / threonine mitogen-activated protein kinases (MAPKs, also known as extracellular signal-regulated kinases, ERKs) by tyrosine kinase receptors (such as EGF receptors) and / or G-protein heterotrimer-associated cellular Factor receptor activation, can interact with a variety of intracellular signals stimulated by different second messengers, phosphorylate and regulate the activities of various enzymes and transcription factors (such as NF-κB, Rsk90, phospholipase A2, c-Myc , CREB, Ets-1, AP-1 and c-jun, etc.). MEKs, also...

Claims

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Application Information

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IPC IPC(8): C07D213/82C07D213/78C07D213/85
CPCC07D213/78C07D213/82C07D213/85
Inventor 贾君磊边林高晓晖
Owner JIANGSU HENGRUI MEDICINE CO LTD
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