肺动脉高压孤儿药Selexipag合成工艺的优化

Synthesis Process Optimization of Orphan Drug Selexipag for Pulmonary Arterial Hypertension

首先,以二苯基乙二酮和2-氨基乙酰胺为原料,通过环合反应和羟基氯代合成了5,6-二苯基吡嗪-2-醇(Ⅰ)和5-氯-2,3-二苯基吡嗪(Ⅱ)。其次,化合物Ⅱ与4-异丙氨基丁醇反应得到4-[(5,6-二苯基-2-基)(异丙基)氨基]-1-丁醇(Ⅲ)。然后,化合物Ⅲ和溴乙酸甲酯发生Willianmson反应得到2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}乙酸甲酯(Ⅳ)。最后,Ⅳ与甲基磺酰胺在叔丁醇钠作用下缩合得到目标产物Selexipag。对各步反应进行了优化,羟基氯代反应条件为:n(Ⅰ)∶n(POCl3)=1.0∶1.7,120℃反应4 h。胺基化条件为:n(4-异丙氨基丁醇)∶n(Ⅱ)=4.0∶1.0,170℃反应68 h。Willianmson反应条件为:n(Ⅲ)∶n(溴乙酸甲酯)∶n(四丁基溴化铵)∶n(氢氧化钠)=1.0∶1.0∶0.1∶15.0,甲苯为溶剂,80℃反应5 h。酰胺化反应条件为:n(Ⅳ)∶n(甲基磺酰胺)∶n(叔丁醇钠)=1.05∶1.0∶1.5,室温反应2 h。优化工艺总收率达到74.5%,且反应条件温和,分离方法简单,适合工业化生产。

First,5,6-diphenylpyrazin-2-ol(Ⅰ)and 5-chloro-2,3-diphenylpyrazine(Ⅱ)were synthesized from diphenylacetophenone and 2-aminoacetamide by cyclization and hydroxyl chlorination.Second,4-[(5,6-diphenyl-2-yl)(isopropyl)amino]-1-butanol(Ⅲ)was obtained by amination reaction of compoundⅡwith 4-isopropylaminobutanol.Then,methyl-2-{(4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butoxy}acetate(Ⅳ)was gained by Willianmson reaction of compoundⅢwith methyl bromoacetate.Finally,the condensation reaction of compoundⅣwith methylsulfonamide in the presence of sodium tert butoxide(NaOtBu)generated the target product selexipag.The reaction steps were optimized.The hydroxyl chlorination was performed at 120℃for 4 h in the molar ratio of n(Ⅰ)∶n(POCl3)=1.0∶1.7.The amination was carried out at 170℃for 68 h in the molar ratio of n(4-isopropylaminobutanol)∶n(Ⅱ)=4.0∶1.0.The Willianmson reaction was proceeded using toluene as a solvent at 80℃for 5 h in the molar ratio of n(Ⅲ)∶n(methyl bromoacetate)∶n(tetrabutyl ammonium bromide)∶n(NaOH)=1.0∶1.0∶0.1∶15.0.The amidation was performed at room temperature for 2 h in the molar ratio of n(Ⅳ)∶n(methylsulfonamide)∶n(NaOtBu)=1.05∶1.0∶1.5.The total yield of the optimized process is up to 74.5%,and the separation method is simple with mild reaction conditions,which is suitable for industrial production.