Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

Abstract

The invention discloses a synthesizing method of an indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride. According to the invention, ethylbenzene I is adopted as a raw material, and a Friedel-Crafts reaction is carried out, such that a compound II is obtained; the compound II is subjected to cyclization, such that ethylindene III is obtained; ethylindene III is subjected to alpha-site oximation reaction, such that a compound IV is obtained; the compound IV is subjected to RaneyNi reduction, such that a compound V is obtained; the compound V is processed with a Tf-protection and sodium borohydride reduction one-pot method, such that a compound VI is obtained; the compound VI is subjected to a Friedel-Crafts reaction, such that a compound VII is obtained; the compound VII is reduced, such that a compound VIII is obtained; and the compound VIII is subjected to protection removing and hydrochloride salt formation, such that a final product compound IX is obtained, and the 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride is obtained. The method provided by the invention is simple and convenient, and has low cost. The content of the product is higher than 99%. The method also has the advantages of low environmental pollution and suitability for industrialized production.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a key intermediate 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride of indacaterol Salt preparation method. Background technique [0002] Indacaterol is a bronchodilator that belongs to the long-acting inhaled β2-agonist (LABA) class and is suitable for the maintenance treatment of adults with chronic obstructive pulmonary disease (COPD). It takes effect in 5 minutes and lasts for 24 hours. Indacaterol is produced by Swiss Novartis Pharmaceuticals, and has been listed in more than 70 countries and regions around the world since 2009; it was approved by the State Food and Drug Administration in June 2012 to be listed in China, with the trade name Angrun ( ), is the first LABA single preparation approved for the treatment of COPD in China. [0003] 5,6-diethyl-2,3-dihydro-1H-inden-2-amine is a key intermediate in the synthesis ...

AI Technical Summary

Problems solved by technology

[0008] Route 1 uses a very expensive raw material: o-diethylbenzene (10,000 yuan per kilogram), a large number of isomers are generated in the second step cyclization reaction, column purification is required, and the Expensive palladium carbon is used as a catalyst and a large amount of sulfuric acid and acetic acid are used as solvents. The economy and environmental friendliness are not good, and it is difficult to industrialize production

Route 2 uses 2-aminoindene, which is also relatively expensive, and uses palladium carbon as a catalyst for the reduction reaction many times in the reaction, which leads to the high cost of the reaction and is not suitable for scale-up production

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