Synthetic process of 5-bromo-7-azaindole

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...

AI Technical Summary

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 or (US2006 / 183758 , 2006) or by derivatization into 5-bromo-7-azaindole (WO2009 / 016460A2). Or 2-amino-3-iodo-5-bromopyridine in palladium catalyst [1,1′-bis(diphenyl Phosphine) ferrocene] palladium dichloride under the action of dichloromethane complex and 2-ethoxyvinyl-1-boronic acid pinacidate to generate 3-position enol derivatives, and then form a ring under the action of hydrochloric acid Obtain 5-bromo-7-azaindole (US2012 / 22258, 2012). The route with 2-amino-5-bromopyridine as the starting material all uses noble metal catalysis, and trimethylethynyl silicon or boron Ester effect, the reaction conditions are relatively mild, but the cost is high

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