Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate

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• 作者：Gary L. Moore ; Rodger W. Stringham ; David S. Teager ; Tai-Yuen Yue
• 刊名：Organic Process Research & Development
• 出版年：2017
• 出版时间：January 20, 2017
• 年：2017
• 卷：21
• 期：1
• 页码：98-106
• 全文大小：326K
• ISSN：1520-586X

文摘

A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol—a key intermediate in the synthesis of darunavir—from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound’s ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.