沙格列汀中间体N-叔丁氧羰基-3-羟基-1-金刚烷基-甘氨酸的合成及其手性拆分

Synthesis and Chiral Resolution of Saxagliptin Intermediate N-tert-butoxycarbonyl-3-hydroxy-1-adamantyl-glycine

本实验的合成方法是以金刚烷甲酸(1)为起始原料,经过氯化亚砜和丙二酸二乙酯的反应,成功合成1-金刚烷甲酸二甲酯(1-金刚烷羰基)丙二酸二甲酯,再经水解、脱羧、高锰酸钾氧化合成的金刚烷甲基酮(2),然后一步一步氧化2-(3-羟基-1-金刚烷基)-2-羰基乙酸(3),2-(3-羟基-1-金刚烷基)-2-羰基乙酸与盐酸羟胺反应(3)的2-(3-羟基-1-金刚烷)-2-乙醛肟酸(4),然后使用Ni-铝合金还原2-(3-羟基-1-金刚烷)-2-乙醛肟酸得到3-羟基-1-金刚烷基甘氨酸,然后用BOC酸酐保守氨基-叔丁基羰基氧-3-羟基-1-金刚烷基-甘氨酸(5)。通过查阅相关文献,探索新的合成DPP-Ⅳ抑制剂沙格列汀重要中间体N-叔丁氧羰基-3-羟基-1-金刚烷基甘氨酸的方法和其手性拆分。得到了新化合物2-(3-羟基-1-金刚烷基)-2-乙醛酸肟(4),以金刚烷甲酸(1)为原料计算总收率可达36%。本实验方法所用原料价廉易得,反应条件温和,操作简便,收率高,适合工业化生产。

In this experiment,adamantane formic acid(1)was used as the starting material,and dimethyl 1-adamantane formate(1-ada-mantane carbonyl)malonate was successfully synthesized by the reaction of thionyl chloride and diethyl malonate.Then adamantane methyl ketone(2)was synthesized by hydrolysis,decarboxylation and potassium permanganate oxidation,and then 2-(3-hydroxy-1-adamantane)-2 was oxidized step by step.2-(3-hydroxy-1-adamantane)-2-acetaldehyde oxime acid(4)obtained by reacting 2-(3-hydroxy-1-adamantyl)-2-carbonyl acetic acid with hydroxylamine hydrochloride(3),then reducing 2-(3-hydroxy-1-adamantane)-2-acetaldehyde oxime acid with Ni-aluminum alloy to obtain 3-hydroxy-1-adamantylglycine.Then amino-tert-butylcarbonyloxy-3-hydroxy-1-adamantyl-glycine(5)was conserved with BOC anhydride.A new method for the synthesis of N-tert-butoxycarbonyl-3-hydroxy-1-adamantyl glycine,an important intermediate of DPP-IV inhibitor saxagliptin,and its chiral resolution were explored through consulting relevant literature.The new compound 2-(3-hydroxy-1-adamantyl)-2-glyoxylic acid oxime(4)was obtained.The total yield calculated from adamantanecarboxylic acid(1)was up to 36%.The raw materials used in this experimental method were cheap and readily available,with mild reaction conditions,simple operation and high yield.It was suitable for industrial production.