新型IDO1抑制剂HS-10319的合成工艺研究

Synthetic process research of a novel IDO1 inhibitor HS-10319

目的优化新型IDO1抑制剂HS-10319的合成工艺。方法以丙二腈为起始原料,经硝化、重排、肟化、脱水缩合、重氮化反应得到4-氨基-N′-羟基-1,2,5-噁二唑-3-亚甲酰氯(4);另以二甲基二硫醚为起始原料,经氧化反应后与二丙酮-D-葡萄糖在碱性条件下反应得到高立体选择性的S构型甲基亚砜化合物(7),7经取代、胺化反应后与中间体4发生取代反应,然后经重排、重氮化、取代、环合、缩合和水解反应得到目标化合物HS-10319。结果与结论目标化合物及其关键中间体的结构经1H-NMR、13C-NMR和MS谱确证,总收率为8.06%(以丙二腈计),纯度为98.9%(HPLC法)。优化后的工艺参数设置合理、工艺稳定性好、产品质量稳定且易于控制,适合工业化生产。

The synthetic pathway of a novel IDO1 inhibitor HS-10319 was optimized in this study.Starting with malononitrile,4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbonyl chloride(4)was obtained through one-pot process and diazotization reaction.Using dimethyl disulfide as the starting material,a highly stereoselective S-configured methyl sulfoxide compound(7)was obtained through oxidation reaction and reaction with diaceton-D-glucose under basic condition.Intermediate 7 was substituted with intermediate 4 after substitution and amination,and then the target compound HS-10319 was obtained through rearrangement,diazotization,substitution,cyclization,condensation and hydrolysis.The structures of HS-10319 and the key intermediates were confirmed by ^(1)H-NMR,^(13)C-NMR and MS.The overall yield was 8.06%(based on malononitrile)with the purity of 98.9%(determined by HPLC).In addition,the corresponding process parameters were determined focusing on the quantity of reagents and the selection of crystallization systems.The improved process has the advantages of optimized process parameters set reasonably,excellent process stability,stable product quality and easy controllability,which is suitable for industrial-scale production and aligned with conventions prevalent in chemical literature.