磷酸奥司他韦起始物料杂质OTg-R1的合成研究

Synthesis of an impurity OTg-R1 in starting material of oseltamivir phosphate

目的:合成磷酸奥司他韦起始物料的杂质OTg-R1。方法:以(-)-莽草酸为起始原料,经酯化反应,戊酮保护、甲烷磺酰保护,在硼烷二甲基硫醚的作用下得到混合物(OSTW-05:OTg-R1=4∶1),再经过KHCO3作用,得到可以经柱层析分离的混合物。经分离得到(3R,4R,5R)-4-(1-乙基丙氧基)-3-羟基5-[(甲基磺酰)氧]-1-环己烯-1-羧酸乙酯。结果:该目标物经质谱(MS),核磁共振氢谱(1H NMR),核磁共振碳谱(13C NMR)确证其化学结构。结论:合成的杂质可作为磷酸奥司他韦起始物料质量控制对照品;本工艺操作可行,原料易得。

Objective:To synthesize an impurity OTg-R1 in a starting material of oseltamivir phosphate.Methods:Using(-)-shikimic acid as a starting material,a mixture(OSTW-05:OTg-R1=4:1)was synthesized via esterification and protection by pentanone and methane sulfonyl,from which impurity OTg-R1could be obtained by column chromatography after KHCO3 under the action of borane dimethyl sulfide.Results:The chemical structure of the OTg-R1 was confirmed by MS,1H NMR and 13C NMR.Conclusion:The synthesized impurity can be used as a reference material for the quality control of oseltamivir phosphate initiation material.This process is feasible and the raw materials are easily available.