Synthesis of a cis 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist

A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an SNAr reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.

本研究报道了一条可制备克级量级盐皮质激素拮抗剂（mineralocorticoid antagonist）3的汇聚式合成路线。以(R)-苯甘氨醇（(R)-phenylglycinol）为起始原料，通过差向异构化反应构建第二个手性中心（stereogenic center），完成了顺式2,5-吗啉（cis 2,5-morpholine）2的合成。后续通过亲核芳香取代反应（SNAr）、达金氧化（Dakin oxidation）、烷基化反应与环化反应的序列步骤，成功完成了拮抗剂3的克级合成，最终得到结晶态固体产物。