非奈利酮的合成

Synthesis of Finerenone

该文合成了糖尿病肾病治疗药物非奈利酮。用3,5,5-三甲基-4,6-二氧杂环己-2-烯-1-酮(16)与3-羟基丙腈反应得到乙酰乙酸2-氰基乙酯(6),然后与4-氰基-2-甲氧基苯甲醛和4-氨基-5-甲基-2-羟基吡啶发生连续的Knoevenagel缩合和Hantzsch环化反应,最后再通过O-烷基化、水解、氨解和手性色谱柱拆分得非奈利酮,总收率30.8%(以16计),纯度99.7%,ee值99.4%。改进后的工艺操作简便、反应温和、收率提高、成本降低。

In this paper,the drug finerenone for diabetic nephropathy treatment was synthesized.Firstly,the intermidate ethyl 2-cyanoacetoacetate(6)was prepared with 3,5,5-trimethyl-4,6-dioxacyclohex-2-en-1-one(16)and 3-hydroxypropionitrile,and then react with 4-cyano-2-methoxybenzyaldehyde and 4-amino-5-methylpyridin-2-ol via continuous Knoevenagel condensation and Hantzsch cyclization,respectively.Finally,finerenone was obtained via O-alkylation,hydrolysis,ammonolysis and chiral column resolution with an overall yield of 30.8%(based on 16),and 99.7%HPLC purity as well as 99.4%ee value.The improved process had the advantages of simple operation,mild condition,high yield and low cost.