The Synthesis Process Of Tadalafil And Its Related Substances Research

Erectile dysfunction(Dysfunction Erectile, ED) is one of the most common sexual dysfunction among middle-aged and elderly men. And it is one of the most common diseases which affects the quality of life of adult men. According to the survey,more than 50% of 38~70 year old men suffer from different degrees of erectile dysfunction. Since the last century since the 90’s, The PDE5 inhibitor, which is representative of the Silidenafil, has significance at anti ED, so more and more researchers began to study PDE5 inhibitors. And the current treatment of ED drugs can be divided into the role of the central drug and the role of drugs in the periphery of the drug, The PDE5 inhibitors effect on the peripheral listed drugs such as Sildenafil, Vardenafil and Tadalafil. Tadalafil is an inhibitor of PDE5 under ICOS and the common development of the company, and is approved in the United States in August 2003, its main indications are erectile dysfunction. In May 2009, second indications, pulmonary arterial hypertensionfor the drug were approved, and was approved for the treatment of benign prostatic hyperplasia in October 2011. It was approved to be listed in China in May 2005. It was showed that Tadalafil global sales reached$21.6 billion in 2013, and it is a typical blockbuster drug. Its product patent has expired in 2015, ED indications patent wil expire in 2020. But the process patent will expire in 2023, so it has important value to research new process to break through patent for tadalafil as soon as possible. On other hand, EP.7.5 has reported nine related substances of tadalafi, of which six complex structures of the material have not been reported in the literature, so it greatly affects the tadalafil in imitation of quality research.In this paper, the first part describes the anti ED drugs and tadalafil background, and review the literatures and patents which have been reported in tadalafil synthetic route.The second part of this paper is about the study on synthesis process of tadalafil, and based on the existing literature, we have optimized the reaction route. In particular, the first step of the Pictet-Spengler reaction, we not only improve the non- selectivity and yield, but also break through the limitation of the patent by using acetonitrile as the solvent. Crystallization refining of the final product, determined the ethyl acetate and water mixed solvent can make API purity of more than 99.95% which through the selection of various solvents.The third part of this paper is about the synthesis of nine related substances reported in EP7.5. Through a variety of routes, we have completed the synthesis of seven compounds, and the other two are still on study.