Synthetic process of 5-bromo-7-azaindole

A technology for the synthesis of azaindole and azaindole, which is applied in the field of synthesis of 5-bromo-7-azaindole, an anticancer drug intermediate, can solve the problems of high cost, high solid waste, and high total cost, and achieve Low cost, simple operation, and short reaction steps

Inactive Publication Date: 2015-03-04
SHANGHAI HUMAN BIOTECH CO LTD
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Problems solved by technology

The route using 7-azaindole as the starting material has the following disadvantages: the price of the starting material is high, the total yield is about 35%, the total cost is high, the solid waste is more, and the operating labor protection conditions are relatively high.
[0006] The other is 2-amino-5-bromopyridine as the starting material (see Scheme 2), and 2-amino-3-iodo-5-bromopyridine is obtained by iodination at the 3-position. 2-amino-3-iodo-5 -Bromopyridine generates 3-alkyne silicon derivatives (WO2011/143422A1) with trimethylethynyl silicon under the catalysis of noble metal palladium reagents such as bistriphenylphosphine palladium dichloride

Method used

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  • Synthetic process of 5-bromo-7-azaindole
  • Synthetic process of 5-bromo-7-azaindole
  • Synthetic process of 5-bromo-7-azaindole

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Embodiment 1

[0025] The first step reaction: preparation of intermediate 2

[0026] In an ice-water bath, 2-amino-3-methyl-5-bromopyridine (10.8 g, 57.8 mmol) was sequentially added into the concentrated sulfuric acid solution (60 mL) solution at one time under mechanical stirring, keeping the temperature below 5°C, Add dropwise pre-cooled caro'sacid (a mixed solution of 86.4mL hydrogen peroxide and 179.2mL concentrated sulfuric acid). After the dropwise addition, remove the ice bath, naturally warm to room temperature, and continue stirring overnight. TLC shows that the raw materials react After completion, the reaction solution was carefully poured into a mixture of ice and water, and sodium hydroxide was added to adjust the alkalinity. A large amount of solids precipitated out and filtered. The filter cake was washed with cold water and dried under vacuum to obtain 9.8g of compound 2, HPLC: 98.3%, yield 78%. 1 H-NMR (400MHz, CDCl 3 ): δ8.620(s, 1H), 8.091(s, 1H), 2.320(s, 3H).

[002...

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Abstract

The invention relates to a synthetic process of 5-bromo-7-azaindole which is an important medical intermediate. The synthetic process comprises the steps of generating 2-nitro-3-methyl-5-bromopyridine from 2-amino-3-methyl-5-bromopyridine by virtue of the oxidation of caro acid, and generating an intermediate 3 under the actions of tetrahydropyrrole and N,N-dimethylformamide dimethyl acetal (DMF-DMA), and finally carrying out reduction and loop closing under the action of a raney nickel/85% hydrazine hydrate system or other low valence metal so as to generate 5-bromo-7-azaindole. The synthetic process is suitable for industrial production and has the advantages that the raw material cost is low, initial raw materials are easily available, and the operation is easy.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, in particular to a synthesis process for anticancer drug intermediate 5-bromo-7-azaindole. Background technique [0002] In recent years, great progress has been made in the research and development of targeted anti-cancer drugs with 7-azaindole as the mother nucleus. 5-bromo-7-azaindole is an important intermediate for the synthesis of such new drugs. 5-bromo- 7-Azaindole can be used to synthesize new drugs such as anticancer drug Vemurafenib (vemurafenib, strong kinase inhibitor), PP121 (cell signaling pathway inhibitor), LKB1 (AAK1 dual inhibitor) (structural formula is as follows). Among them, vemurafenib is a strong kinase inhibitor, which is specially developed to target the BRAFV600 mutation in cancer cells. The US Food and Drug Administration (FDA) approved vemurafenib on August 17, 2011 for patients with unresectable or metastatic BRAFV600E mutant melanoma. [0003] [00...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 宋绍兴
Owner SHANGHAI HUMAN BIOTECH CO LTD
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