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

Abstract

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.

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…Nonstereoselective synthesis of protected analogues of 364 required additional (enzymatic) resolution or down-stream purification of 3-OH-bis-THF. 471 Complementary to a complex stereoselective chemical synthesis of the desired (2S,3R)-364, [472][473][474] an enzymatic aldol addition would pose an interesting short synthetic strategy. With various examples discussed throughout this manuscript, biocatalytic carboligation has clearly been shown to be a powerful tool capable of rapidly accessing the complex architectures present in both anti-viral nucleoside analogues and peptidomimetics.…”

Sugar Alcohols and Organic Acids Synthesis in Yarrowia lipolytica: Where Are We?

“…iCA is also used as a synthon in the chemical and pharmaceutical industries [53]. For instance, potassium isocitrate is used for the synthesis of HIV protease inhibitors Darunavir and Brecanavir [54]. In rats, the ability of iCA to mitigate the neurotoxic effects of molybdenum and lead has been demonstrated [50].…”

“…A similar effect was observed for oxalic acid, however in a lesser extent (70.0 and 23 g/L, respectively). With the Y. lipolytica wild-type strain 704, an iCA titer of 66 g/L was obtained with a ratio iCA/CA of 4:1 [56], while with repeated batch cultures of the strain VKM Y-2373 in a 10-L bioreactor, iCA titer of 109.6 g/L was obtained with a yield of 0.8 g/g ethanol and productivity of 1.35 g/(L•h) [54]. During trials in a 150-L bioreactor using the Y. lipolytica strain 704 grown in media based on paraffins and ammonium sulfate as carbon and nitrogen sources, an iCA titer of 84 g/L was obtained with a yield of 1.2 g/g after 3 days of culture [58].…”

Comparing the greenness and sustainability of three routes to an HIV protease inhibitor intermediate

“…2,3 A cost analysis of various synthetic pathways to darunavir showed that the bis-THF alcohol moiety contributed to roughly half the cost of synthesizing the active ingredient. 4 This explains why numerous routes for its synthesis have been described. 2,3,[4][5][6][7][8][9][10][11][12][13] In this study we have assessed the greenness and sustainability of the three most recent and innovative routes.…”

“…2,3,[4][5][6][7][8][9][10][11][12][13] In this study we have assessed the greenness and sustainability of the three most recent and innovative routes. 3,4,13 Publication in 1992 of the amounts of waste generated per kg of product (The (E)nvironmental Factor), in various sectors of the chemical industry (Table 1), 14 served to focus attention on the high E-factors observed in pharmaceuticals manufacture. Furthermore, in 2012 it was estimated that branded and generic pharmaceutical industries produce ≥100 million kilograms of Active Pharmaceutical Ingredient (API) and more than 15 billion kilograms of co-produced waste per annum.…”