Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine

Abstract

The invention relates to a novel method for synthesizing an important intermediate 6-chloro-5-fluoroindole for anticancer and weight-reducing medicines. The method comprises the steps that: 3-chloro-4-fluoroaniline is reacted with boron trichloride in a toluene solution under the action of a Lewis acid aluminium trichloride to produce imine which is then hydrolyzed under the action of hydrochloric acid to get an intermediate, a target product is generated by the reduction of the intermediate by sodium borohydride in a dioxane/water system and then by reflux dewatering, and the 6-chloro-5-fluoroindole is produced by reduced pressure distillation of the initial product. The method has the advantages of readily available raw materials, short reaction steps and low costs, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of fluorine-containing indole as a pharmaceutical intermediate, and in particular relates to a new method for 6-chloro-5-fluoro-indole as an anticancer and weight loss pharmaceutical intermediate. Background technique: [0002] At present, 6-chloro-5-fluoroindole is a novel 5-HT2C receptor agonist-Ro 60-0715 (J.Med.Chem., 1997, 40(17), 2762-2769; Bioorganic & Medicinal Chemistry Letters, 2004, 14(9), 2367-2370), the compound can selectively inhibit 5-HT2C, which has epoch-making significance for reducing obesity, and is crucial for reducing diseases caused by obesity; 6 -Chloro-5-fluoroindole is also an important intermediate for the synthesis of new anticancer drugs such as glycogen synthase kinase 3β (glycogen synthase kinase 3β, GSK-3β) inhibitors (J.Med.Chem.2009, 52, 1853- 1863), as the research and development of new drugs against colon cancer and pancreatic cancer related to it enters the clinical stage, the i...

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Problems solved by technology

[0006] Although Document 3: (Synthetic Communications; 2004; 34 (12); 2295-2300), improved the method of Documents 1 and 2 and replaced DMF-DMA with DMF-DIPA in the fourth step reaction, the amount of by-products was reduced. reduction, but the synthesis process still has the disadvantages of greater pollution and higher cost

In addition, there are 6-chloro-5 fluoroindole derivatives substituted with 2-carboxylic acid first, followed by decarboxylation at high temperature. The yield of this method is low, and the reaction conditions are harsh and unsuitable for industrial scale-up (such as US5494928)

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