Synthesis And Process Optimization Of Important Intermediates Of Avanafil

Avanafil, was a new drug for the treatment of erectile dysfunction(ED) in the United States, which was approved by the Food and Drug Administration(FDA) of United States on April 27, 2012. Compared with Commercially available Sidelnafil, Vardenafil, Tadalafil, Udenafil, Mirodenafil, it has the advantages of high selectivity to Phosphodiesterase 5(PDE5), short half-life, patience and strong, side effects, etc. Therefore,Avanafil will have broad application prospects in terms of the treatment of ED. We carried out a process optimization for the important intermediates(such as ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate, ethyl(S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl, pyrimidin-2-ylmethanamine)pyrimidine-5-carboxylate)of the synthetic route of the Avanafil, by changing the experimental conditions and the use of orthogonal experimental design and response surface design methods. We synthesized some of the intermediates analogs, and it has important significance for its research and development of similar drugs. Focusing on the synthesis and process optimization of important significance of Avanafil, following has been carried out.Firstly, synthesis and process optimization of ethyl 4-hydroxy-2-(methylthio)-pyrimidine-5-carboxylate.ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate was synthesized from S-methylisothiourea hemisulfate salt and diethyl ethoxymethylenemalonate in ethanol. The feed ratio, reaction temperature, reaction time and other factors were optimized to improve the yield. The target products were characterized by 1H NMR, 13 C NMR, ESI-MS, IR, melting point.Secondly, synthesis and process optimization of ethyl(S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl and analogues.First of all, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate was synthesized from ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate and phosphorus oxychloride. Then, it react with(3-chloro-4-methoxyphenyl)methanamine produced ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate(6). Sulfone and sulfoxide, Oxidized from compound 6 by green oxidant hydrogen peroxide, react with L-prolinol and produced(S)-4-((3-chloro-4- methoxybenzyl) amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl(9). At last, We carried out a process optimization from compound 6 to compound 9, by changing the experimental conditions and the use of orthogonal experimental design and response surface design methods. The target products were characterized by 1H NMR, 13 C NMR, ESI-MS, IR, melting point.Thirdly, synthesis and process optimization of pyrimidin-2-ylmethan- amine)-pyrimidine-5-carboxylate.pyrimidin-2-ylmethan- amine)- pyrimidine-5-carboxylate was synthesized from pyrimidine-2-carbonitrile by trying different reduction system. The amount of the reducing agent, reaction temperature, reaction time and other factors were optimized by experimental design and response surface design methods to improve the yield. The target products were characterized by 1H NMR, 13 C NMR, ESI-MS, IR, melting point.