Synthesis Of Key Intermediates Of Selexipag And Synthesis Of Related Substances

Selexipag is an oral,long-acting,highly selective prostacyclin receptor agonist for the treatment of pulmonary hypertension（PAH）.Selexipag is rapidly hydrolyzed into an active metabolite in the body,and the active metabolite has a higher specific selectivity for the prostacyclin receptor and is 37 times more potent than selexipag.Therefore,selexipag has brought new treatment options to PAH patients,and has good market prospects.On the basis of the literature,a new route to synthesis the key intermediates of selexipag,using 5,6-diphenylpyrazin-2-one as raw material,was studied in this paper.Firstly,5,6-diphenylpyrazin-2-one was reacted with 4-nitrobenzene-1-sulfonyl chloride,methanesulfonyl chloride,and 4-methylbenzene-1-sulfonyl chloride to form the corresponding sulfonate compound 2,compound 3,and compound 4.Compound 2 and compound 3 were reacted with 4-（isopropylamino）-1-butanol to form5,6-diphenyl-2-hydroxypyrazine.The compound 4 is reacted with4-（isopropylamino）-1-butanol,and DMF,DMSO,DMAC and NMP were used as solvents to form 5,6-diphenyl-2-hydroxypyrazine,a small amount of target intermediate is produced.The compound 4 is reacted with 4-（isopropylamino）-1-butanol,DMF is used as a solvent,and KI is a base,which mainly produces 5,6-diphenyl-2-hydroxypyrazine,target intermediate 4-[（5,6-diphenylpyrazin-2-yl）（isopropyl）amino]-1-butanol accounts for 10%.In this paper,six related substances contained in selexipag were synthesized,n amely N-（4-（（5,6-diphenylpyrazin-2-yl）oxy）butyl）-N-isopropyl-5,6-diphenylpyrazin-2-a mine（A）,4-（（5,6-diphenylpyrazin-2-yl）oxy）-N-isopropylbutan-1-amine（B）,4-（（5,6-dip henylpyrazin-2-yl）（isopropyl）amino）butyl-2-（methylsulfonamido）acetate（C）,2-（4-（（5,6-diphenylpyrazin-2-yl）（isopropyl）amino）butoxy）acetic acid（D）,2-（4-（（5,6-diphenylpyraz in-2-yl）（isopropyl）amino）butoxy）acetamide（E）,2-（4-（（5,6-diphenylpyrazin-2-yl）（isopro pyl）amino）butoxy）acetate（F）.The chemical structures were confirmed by IR,¹H-N MR,¹³C-NMR and MS.