奥贝胆酸合成工艺优化

Improved Synthesis of Obeticholic Acid

本研究对奥贝胆酸(1)的合成工艺进行了优化。3α-羟基-7-氧代-5β-胆烷酸(2)经酯化和3-位硅烷化得3α-三甲基硅氧基-7-氧代-5β-胆烷酸甲酯(4)。以三氟甲磺酸三甲基硅基酯代替传统的烯醇化试剂三甲基氯硅烷,在-10℃即可将4完全转化为3α,7-二(三甲基硅氧基)-6-烯-5β-胆烷酸甲酯(5),收率由64.3%提高至98.0%。使用三氟化硼乙腈代替三氟化硼乙醚作羟醛缩合剂,使5与乙醛反应得3α-羟基-6-亚乙基-7-氧代-5β-胆烷酸甲酯(6),收率由70.0%提高至93.2%。6经加氢还原、水解和7-位羰基还原得1。优化后的工艺操作简便,反应条件温和,成本低,总收率由24.6%提高至73.6%(以2计)。

The synthetic process of obeticholic acid（1） was improved. Methyl 3α-[（trimethylsilyl）oxy]-7-oxo-5β-cholanate（4） was synthesized via esterification and silicon alkylation from 3α-hydroxy-7-oxo-5β-cholanic acid（2）.Compound 4 was completely converted to methyl 3α,7-di[（trimethylsilyl）oxy]-5β-cholanate（5） at -10 ℃ , and the yield was increased from 64.3% to 98.0% by using trimethylsilyl triflate as the enolization reagent. Then 5 reacted with acetaldehyde in the presence of boron trifluoride acetonitrile complex to give methyl 3α-hydroxy-6-ethylidene-7-oxo-5β-cholanate （6） in a yield of 93.2% , which was 23.2% higher than the literature. Then 6 was subjected to hydrogenation,hydrolysis and carbonyl reduction to provide 1. The improved synthetic route simplified the reaction conditions and operation procedure, and also gave a better overall yield of 73.6% （based on 2）with a purity of 99.0% .