Study On The Synthetic Process Of Arotinolol Hydrochloride And The Synthesis Of The Related Substances

Arotinolol hydrochloride is a β-selective adrenoceptor antagonist used for the treatment of mild to moderate essential hypertension and angina.At the present, arotinolol hydrochloride all in Chinese market were imported from abroad, because there is no legal source of active pharmaceutical ingredient in China. To break the foreign monopoly, it is very important to study on the synthetic process of arotinolol hydrochlorideIn this paper, a synthetic route of arotinolol hydrochloride was chosen from all the reported processes, firstly 5-(2-mercaptothiazol-4-yl)thiophene-2-carboxamide is directly reacted with epichlorohydrin to give the corresponding epoxide, sencondly the resulting epoxide is then reacted with tert-butylamine to yield arotinolol, finally arotinolol is reacted with hydrochloric acid to yield arotinolol hydrochloride. After the optimization of reaction conditions, so that the total yield was up to 60%,significantly higher than the yield of the reported. the purity of the product was higher than 99%(HPLC), and the content of single impurity was less than 0.1%.. The chemical structure of arotinolol hydrochloride had been characterized by means of 1H-NMR and MS.Based on the structures of 6 imprities which may be present, the sources of their generations were analyzed. Then the synthetic routes were designed and tried, finally 1 impurities of them were obtained and the chemical structures were comfirmed by 1H-NMR and MS.Based on the results of the small-scale experiments, the synthesis process of the pilot-scale experiments were followed and it was proved to be validated. The stability and maneuverability of the synthesis process in industrial scale production was further to verified in a plant trial production, the results proved feasible and laid technical foundation for the commercial batch production of arotinolol hydrochloride.