Study On The Synthesis Of Selexipag

As a oral selective agonists of the（IP）receptor,selexipag was used for the treatment of pulmonary arterial hypertension（PAH）.Selexipag was hydrolyzed by carboxylesterase to yield its active metabolite in the human body,which can delay disease progression and reduce the risk of hospitalization for PAH.Therefore,selexipag has broad market prospect.In accordance with“new drug（Western medicine）pre-clinical pharmacy research guidelines”,the synthetic route of selexipag were systermatically studied in this paper.Firstly,the original research patent was verified by experiment first,and purification of the final product by column chromatography was changed.However,there were aslo some problems that could not be resolved effectively,such as one of the reagents was sensitive to temperature and humidity,low product purity,etc,which led to the industrialization can not be achieved.So,we designed a new synthetic route,and accessed to this route for the industrialization through the laboratory research according to the principle of retro synthetic analysis.The new route was as follows:Benzil was subjected to cyclization with glycinamide hydrochloride（compound S-2）,which was chlorinated to 2-chloro-5,6-di phenylpyrazine（compound S-4）,and 4-（isopropyla mino）butanol（Compound S-5）was reacted with compound S-4 to give 4-[（5,6-diphenyl-2-pyrazinyl）（1-methylethyl）amino]-1-Butanol（Intermediate I）.Selexipag was obtained from Williamson reaction between Intermediate I with compound S-7.The purity of the selexipag was above 99.9%（HPLC）,and the content of a single impurity was less than 0.05%;the total yield for this route was14.2%.The structure of final product and the key intermediate were confirmed through IR,¹H-NMR,¹³C-NMR.According to the preparation demand for the crystal form of the bulk drug of selexipag,we had got one crystal form of selexipag,which showed diffraction peak in the power X-ray diffraction spectrum at the following angles of diffraction 2θ:8.90°,12.74°,16.82°,20.62°,22.46°.