Study On The Synthesis Of Arotinolol Hydrochloride

Arotinolol hydrochloride,a new combinedαandβadrenoceptor blocking agent,was developed by Sumitomo Pharmaceutical Corporation,and first launched as Almarl in Japan in 1985 for the treatment of mild and moderate essential hypertension,essential tremor,angina,and tachycardia arrhythmia.Different kinds ofβ-adrenoceptor blocking agents and their clinical application were briefly reviewed,and some common-used drugs were listed in the thesis.Starting from thiophene-2,5-dicarboxylic acid,Arotinolol hydrochloride was prepared via a 9-step sequence such as esterification,hydrolysis,bromination and condensation with a total yield of 29.6%.The structure of the target compound and some important intermediates was determined by ~1H NMR, and MS spectra.5-acetylthiophene-2-carboxamide(14)was synthesized via ammonolysis from methyl 5-acetylthiophene-2-carboxylate(31)in good yield while it was reported to be obtained from 5-acetylthiophene-2-carbonyl chloride(13)in toxic toluene.After intensive investigation, compound 31 was concisely synthesized from diethyl thiophene-2,5-dicarboxylate(29)via one-pot procedure consisting of 3 steps of reactions in an overall yield of 75.3%.This improved approach has an economic advantage for further scale-up purpose after the reactions were here optimized.