Method for synthesis of dronedarone

Abstract

The invention relates to a method for synthesis of dronedarone. The method comprises the following steps that 1), p-nitrophenol, paraformaldehyde and concentrated hydrochloric acid as raw materials undergo a condensation reaction in the presence of concentrated hydrochloric acid or phosphoric acid as a catalyst to produce 2-chloromethyl-4-nitrophenol; 2), 2-chloromethyl-4-nitrophenol and triphenylphosphine undergo a reflux reaction in the presence of chloroform to produce 2-hydroxy-5-nitrobenzyl-triphenyl-phosphonium chloride, and 3), 2-hydroxy-5-nitrobenzyl-triphenyl-phosphonium chloride and n-valeryl chloride undergo a condensation reaction in a toluene solution in the presence of triethylamine and n-pentanoic acid as catalysts to produce 2-(n-butyl)-5-nitrobenzofuran.

Description

technical field [0001] The present invention relates to a synthesis process route of the pharmaceutical compound dronedarone, in particular to the process conditions and methods for preparing corresponding intermediates in the process route. Background technique [0002] The chemical structure of dronedarone (common name: Dronedarone) is similar to the standard drug amiodarone for the treatment of atrial fibrillation, and the mechanism of action is the same, both of which are potassium ion channel blockers. European patent EP471609 reports that dronedarone has special significance as an antiarrhythmic drug, which can significantly reduce the morbidity and mortality of paroxysmal or persistent atrial fibrillation or atrial flutter; and can effectively prevent certain types of myocardial infarction Clinically, its hydrochloride, namely dronedarone hydrochloride, is usually used clinically. [0003] In the process of preparing dronedarone, 2-n-butyl 5-nitrobenzofuran is a key ...

AI Technical Summary

Problems solved by technology

[0012] Route (1) involves cumbersome operations in literature reports and the yield is very high, and the reproducibility of the reaction is poor; although the steps of route (2) are short, more expensive catalysts are used, and it is not easy to carry out large-scale production; The route (3) has a long step and a low yield; the route (4) has a long step and a large amount of mixed acid is used in the nitration process, which is not conducive to the treatment of the three wastes. In addition, the yield of the whole route is not high

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