苏沃雷生的合成  

Synthesis of Suvorexant

作　　者：杨媛媛 张志光 李明乐 张勇[1,2] YANG Yuanyuan;ZHANG Zhiguang;LI Mingle;ZHANG Yong(School of Chemical and Pharmaceutical Engineering,Hebei University of Science and Technology,Shijiazhuang,Hebei 050018,China;State Key Laboratory Breeding Base-Key Laboratory of Molecular Chemistry for Drug of Hebei Province,Shijiazhuang,Hebei 050018,China)

机构地区：[1]河北科技大学化学与制药工程学院,河北石家庄050018 [2]河北省药用分子化学重点实验室-省部共建国家重点实验室培育基地,河北石家庄050018

出　　处：《河北科技大学学报》2020年第2期158-163,共6页Journal of Hebei University of Science and Technology

基　　金：河北省自然科学基金(B2019208137)。

摘　　要：为了改进苏沃雷生的合成路线,简化实验操作,完善中间体理化性质及图谱数据,对其合成方法进行了研究。以2-氨基-5-甲基苯甲酸为起始原料,依次经过重氮化反应、碘代反应、Ullmann反应、酰胺化反应、脱保护反应、亲核取代反应得到目标化合物。通过优化合成方法,使用重结晶代替柱层析纯化,直接得到中间体及目标化合物。结果表明:重氮化反应和碘代反应中,以盐酸水溶液为溶剂,n(2-氨基-5-甲基苯甲酸)∶n(亚硝酸钠)∶n(碘化钾)=1∶1.2∶1.4时,收率为92.31%;Ullmann反应中,以N,N-二甲基甲酰胺为溶剂,n(2-碘-5-甲基苯甲酸)∶n(2H-1,2,3-三氮唑)∶n(碘化亚铜)=1∶2∶0.05时,收率为63.47%;脱保护反应中,以乙腈为溶剂,n((R)5-甲基-4-(5-甲基-2-(2 H-1,2,3-三唑-2-基)苯甲酰基)-1,4-二氮杂-1-羧酸叔丁酯)∶n(对甲苯磺酸)=1∶1.2时,收率为93.02%;优化后,总收率为47.99%,产品纯度为99.89%,目标化合物经1H-NMR和13 C-NMR得到结构确证。新的合成路线反应条件温和,实验操作及后处理简单,适合工业化生产。In order to explore the synthetic route of Suvorexant,simplify experimental process and clarify the physicochemical properties and spectral data of intermediates,the synthetic method of Suvorexant was studied.The target compound was synthesized from 2-amino-5-methylbenzoic acid,followed by diazotization reaction,iodination reaction,Ullmann reaction,amidation reaction,deprotection reaction,and nucleophilic substitution reaction.By optimizing the synthesis parameters,Suvorexant and intermediates can be directly obtained by using recrystallization method instead of column chromatography purification.The results show as follows:Hydrochloric acid aqueous solution is used as the solvent in the diazotization reaction and the iodination reaction,n(2-amino-5-methylbenzoic acid)∶n(sodium nitrite)∶n(potassium iodide)=1∶1.2∶1.4,the yield is 92.31%;N,N-dimethylformamide is used as the solvent in the Ullmann reaction,n(2-iodine-5-methylbenzoic acid)∶n(2H-1,2,3-triazole)∶n(copper iodide)=1∶2∶0.05,the yield is 63.47%.Acetonitrile is used as the solvent in the deprotection reaction,n((R)5-methyl-4-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diaza-1-carboxylic acid tert-butyl ester)∶n(p-toluenesulfonic acid)=1∶1.2,the yield is 93.02%.The total yield of the route is 47.99% after optimization,and the purity is 99.89%.The structure of the target compound is confirmed by 1H-NMR and 13 C-NMR.The optimized route has advantages of mild reaction conditions and simple process and workup operation,which is suitable for industrial production.

关 键 词：有机合成化学 苏沃雷生 失眠症 食欲素受体拮抗剂 ULLMANN反应 

分 类 号：R971.3[医药卫生—药品]