An Explore To New Routes Of Synthesising Dronedarone Hydrochloride Analogue

In this thesis we have desighned a new route to synthesize antiarrhythmic drug dronedarone hydrochloride analogues. Dronedarone hydrochloride is a new antiarrhythmic drug developed by French Company Sanofi-Aventis. It was first listed in July2009approved by the FDA (Food and Drug Administration) of the United States, with a structure similar to amiodarone. Both of amiodarone and dronedarone are benzofuran derivatives, but there is no iodo substituent in the dronedarone molecule, which reduced iodine toxicity while maintaining the therapeutic effect of amiodarone.Dronedarone applies to rhythm control of atrial flutter and atria] fibrillation, ventricular arrhythmia and slowing maintain sinus rhythm, clinically used for the treatment of cardiac arrhythmias. So the research and development of dronedarone will bring great social and economical benefits.In this route we intend to use4-hydroxyacetophenone as a starting material. After the first step of Claisen ester condensation with pentanoate under alkaline conditions to form1-(4-hydroxyphenyl) heptane-1,3-dione, following is an SN2reaction with1-bromo-3-chloropropane. The intermediate generated is then reacted with N-methanesulfonyl-p-benzoquinoneimine, and a dominoreaction of Michael addition and an intramolecular cyclization reaction occurs to form a benzofuran derivative. After that, this benzofuran derivative is then involved in another SN2reaction with di-N-butylamine to give dronedarone, which is acidified to obtain the target product dronedarone hydrochloride under the condition of hydrochloric acid.But in the course of the study, we found that the structure of1,3-diketone intermediate has a decisive impact on the structure of the product. When the terminal substituent of1,3-dione is methyl, the product is the expected3-benzoyl-2-alkyl benzofuran derivatives, but when the terminal substituent is butyl, the regioselectivity of the intramolecular ring-forming reaction is changed, the carbonyl group next to the phenyl group is preferentially attacked, generating3-valeryl-2-phenyl-benzofuran derivatives.The reactions involved in this route avoid using of toxic reagents and heavy metal catalysts such as palladium or copper. The raw materials are easy to get. Operations are simple while the route is also short, greatly reduced the cost of production.