3-(N,N-Dimethylamino)-1-(2-thienyl)propan-1-ol (6), prepared from 2-acetylthiophene (4) in a two-step overall yield of 79%, is resolved into (S)-6 of 93% ee as its diastereomeric salt (8) with (S)-mandelic acid (7) according to Eli Lilly's procedures developed for the resolution-racemization-recycle (RRR) synthesis of duloxetine (2) with some modifications in terms of practicality. On its liberation from 8, (S)-6 undergoes Ndemethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O-ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N-methyl group. Alkaline hydrolysis then affords (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol (1) of 100% ee, an alleged penultimate precursor to duloxetine (2), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t-BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2.
This report deals with enantioselective synthesis of viracept 1 (nelfinavir mesylate, AG 1343), a potent HIV protease inhibitor, and 3-hydroxytetradecanoic acid 3, a component of lipid A comprising lipopolysaccharide embedded in the cell surface of Gram-negative bacteria, from both strategic and practical perspectives. As regards the synthesis of 1, the synthetic approaches to its central intermediate 2 possessing the common structural motif of 1,4-differentially substituted-2-amino-3-hydroxylbutane are mainly discussed with emphasis on the molecular symmetry that has helped streamline the synthetic strategy. In the discussion of the synthetic strategies to access a single enantiomer of 3, the chiral methodologies that have been applied so far are assessed for industrial viability; the synthetic alternatives explored include resolution via diastereomeric salt formation, lipase-catalyzed kinetic resolution, asymmetric synthesis, and chiral pool approaches.
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