2-(3-羟基-1-金刚烷基)-2-氧代乙酸的合成

Synthesis of 2-(3-Hydroxy-l-adamantane)-2-oxoacetic acid

1-金刚烷甲酸经混酸氧化得3-羟基-1-金刚烷甲酸,经酰氯化、丙二酸二乙酯取代、硫酸/冰醋酸脱羧及羟基化,"一锅法"制得3-羟基-1-金刚烷甲基酮,经高锰酸钾氧化得沙格列汀关键中间体2-(3-羟基-1-金刚烷基)-2-氧代乙酸。本研究还对"一锅法"的具体过程分步研究并进行结构确证。优化过的路线试剂价廉易得,条件温和,操作简便易控,总收率约61%(以1-金刚烷甲酸计)。

1-Adamantanecarboxylic acid was oxidized by a mixture of sulfuric acid and nitric acid to afford 3-hydroxy-1-adamantanecarboxylic acid, after using a one-pot method, including acylation, substitution by diethyl malonate, decarboxylation and hydroxylation reaction, 3-hydroxy-1-acetyladamantane was obtained. The latter was subjected to oxidation reaction with potassium permanganate to give the key intermediate of saxagliptin： 2-（3-hydroxy-1-adamantyl）-2-oxoacetic acid with an overall yield of about 61%（based on 1-adamantanecarboxylic acid）. The improved route has several advantages, such as common and inexpensive reagents, mild reaction conditions, simple operations, etc.