1P10: h) Synthesis of versatile route to arylthiomethyl morpholine analogues of reboxetine

J. Boot et al.³⁸ worked on a novel arylthiomethyl morpholines, a potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/ norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.Reaction between benzaldehyde and the enolate derived from readily available N-benzyl-2-morpholinone (34) gave an acceptable yield of the two diastereomeric benzylalcohols (35) and (36) in a ratio of 2.2/1 (Scheme 10).³⁹ The aldol products could be separated by chromatography on silica gel. The assignment of relative stereochemistry was based on the coupling constants between the proton at C-2 of the morpholine ring and the benzylic hydrogen. The initial assignment of the relative stereochemistry was later confirmed by X-ray crystallographic analysis.⁴⁰ Diborane-mediated reduction of the lactam gave morpholine benzyl alcohols (37) and (38) in good yield.

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38. J. Boot, M. Cases, B. P. Clark, J. Findlay, P. T. Gallagher, L. Hayhurst, T. Man, C. Montalbetti, R. E. Rathmell, H. Rudyk, M. W. Walter, M. Whatton, and V. Wood, Bioorg. Med. Chem. Lett., 2005, 15, 699.

39. A. Dobrev, L. Nechev, and K. Ivanov, Liebigs Ann. Chem., 1989, 815.

40. For details see: M. W. Walter, B. P. Clark, P. T. Gallagher, H. L. Haughton, and H. C. E. Rudyk, WO 2004017977NET assay: J. Gobel, D. L. Saussy, and A. Goetz, J. Pharmacol.Toxicol. Methods, 1999, 42, 237; SERT/DAT assay: S. Ramamoorthy, E. Giovanetti, Y. Qian, and R. Blakely, J. Biol. Chem., 1998, 273, 2458.


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