Studies On The Synthesis Of Roflumilast And Its Impurities

Chronic obstructive pulmonary disease is a kind of characteristic of airflow obstruction in chronic bronchitis and emphysema, as a kind of severe lung disease, the disease is gradually becoming a global public health problem. It is projected that by 2030 chronic obstructive pulmonary disease will rank jump to the third leading cause of death. Modern pharmacology therapy in the treatment of chronic obstructive pulmonary disease has certain limitations, especially in the area of reduce the disease progressive strengthening.Roflumilast, as a new type of targets of the second generation of selective phosphodiesterase 4 inhibitors, is gradually come to the attention of researchers. Meanwhile, roflumilast, as the only listed phosphodiesterase 4 inhibitor, gradually become the focus of competition to generic.In this paper, on the basis of the traditional four synthetic routes, we selected a simple method of synthesis of Roflumilast.In the optimization process of synthetic route, we found seven kinds of impurityies, and their structures were confirmed by high performance liquid chromatography, infrared absorption chromatography, ultraviolet absorption chromatography, nuclear magnetic resonance hydrogen spectrum, carbon nuclear magnetic resonance spectrum and mass spectrum characterization. At the same time, we also discussed the source of these impurities. After a series of optimization for the synthetic process, the content of impurities dropped to the lowest line.At last, in the crude product, the content of roflumilast was more than 99.96%, the content of single impurity(0.01% and 0.02%) fell to below 0.1%, and the content of total impurity(0.04%) was less than 0.3%. These results were conformed to ‘The technology guiding principles of the study on chemical impurities' which was issued by ‘State Food and Drug Administration'. In addition, the synthetic process was approved by ‘Tianjin review center for examination of new drugs', and ‘roflumilast tablet' belongs to the state of 3.1 class of new drugs.