Study On The New Synthetic Process Of Selexipag

Pulmonary artery hypertension is a chronic,progressive malignant pulmonary vascular disease,which is usually called as"cardiovascular cancer".Its incidence is hidden,and the mortality rate is very high.2-[4-[N’-（5,6-Diphenylpiperazin-2-yl）-N’-isopropylamino]butoxy}-N’-（methylsulfonyl）acetamide（Selexipag,IUPAC）is a new and highly active IP receptor agonist drug.Its convenient oral dosage form and long-lasting medicinal effect bring dawn to patients with different pulmonary artery hypertension.In this paper,based on the traditional synthesis methods,a new synthetic route was designed.Benzil and glycinamide was utilized as starting substrates,crude Selexipag was obtained through five reaction steps:nucleophilic addition,halogenation,nucleophilic substitution,condensation,and amide condensation.Finally,the pure drug was obtained with desired crystal after recrystallization.The influence factors of the reaction conditions such as reaction time,reaction temperature,and materials’ratios were investigated.The experiments show that the optimal process conditions for the synthesis of5,6-diphenyl-2-hydroxypyrazine was obtained as follows:with a loading ratio of n（benzoyl）:n（glycinamide）=1.0:1.2,the reaction was carried out at about 65℃for 12 h and affored the desired product in 92%yield;the optimal process conditions for the synthesis of5-bromo-2,3-diphenylpyrazine was obtained as follows:with a loading ratio of n（5,6-diphenyl-2-hydroxypyrazine）:n（phosphoryl bromide）=1.0:2.0,the reaction was carried out at about 70℃for 23 h and affored the desired product in 91%yield;the optimal process conditions for the synthesis of N-isopropyl-5,6-diphenylpyrazine-2-aminewas obtained as follows:with a loading ratio of n（5-bromo-2,3-diphenylpyrazine）:n（isopropylamine）=1.0:2.0,K₂CO₃ was addied as acid binding agent and the reaction was refluxed for 12 h,afforded the desired product in 63%yield;the optimal process conditions for the synthesis of2-{4-[N’-（5,6-diphenylpyrazin-2-yl）-N’-isopropylamino]butoxy}acetic acid was obtained as follows:with a loading ratio of n（N-isopropyl-5,6-diphenylpyrazine-2-amine）:n（bromoacetic acid）:n（4-chlorobutanol）=1.0:3.5:2.5,the reaction was carried out at about 30℃for3h～4hand affored the desired product in 53%yield;A better process for the synthesis of Selexipag obtained as follows:with a loading ratio of n（2-{4-[N’-（5,6-diphenylpyrazin-2-yl）-N’-isopropylamino]butoxy}acetic acid）:n（CDI）:n（DBU）:n（methylsulfonamide）=1.0:1.5:1.2:1.5,the reaction was refluxed for 12 h and afforded the desired product in 94%yield,the preferred process condition for the preparation of Selexipag crystal typeⅠwas recrystallization from 4 volumetric equivalents of ethanol.The crystallization began at 40℃～50℃by gradient cooling with rate of 10℃?h^-1,and then a cooling rate of 5℃?h^-1 was utilized until the temperature reached to 0℃～10℃.By this process a yield of 74%in one run was achieved.To develop a practical process for industry-scale production,a new synthetic routefor Selexipag was investigated.This protocol has some merits including economical efficiency,simpleprocess and free of dangerous step.The desired product was obtained with high purity and superior medicinal crystal form,which has important application prospects.