Paroxetine 1 is a selective serotonine-reuptake inhibitor (Paxil, Seroxat) used in the treatment of depression¹ and Parkinson's disease². Its industrial synthesis³ proceeds via racemic trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine which undergoes optical resolution to provide a desirable (3S,4R)-enantiomer 2a and its antipode 2b whose enantiomeric purity can be improved by a reverse enrichment procedure.⁴

Transformations of 2b proceeding through 'temporary destruction' of asymmetric centres is challenging particularly in respect to the possibility of converting the unwanted (3R,4S)-enantiomer into the desirable one with the opposite absolute configuration.

The more accessible of the two chiral centers in 2b appears to be that on C-3. It can be readily attacked by a strong base in an elimination reaction to furnish (4S)-4-(4-fluorophenyl)-3-methylene-1-methylpiperidine 7b which can be further transformed into an achiral intermediate 8 (Fig. 1).

In an attempt to improve the yields of elimination we decided to employ a supported solvent-free microwave methodology.⁶ Dehydration of 2b was attempted on acidic clays (KSF, K-10) and calcined alumina, on basic alumina, basic alumina impregnated with KF, neutral alumina and neutral alumina/KF under microwave irradiation.

Figure 1.

References:

1) Mathis, C. A., Gerdes, J. M.., Enas, J. D., Whitnay, J. M., Taylor, S. E., Zhang, Y., McKenna, D. J., Havlik, S., Peroutka, S. J. Pharm. Pharmacol. 1992, 44, 801. 2) Keverline-Frantz, K., Boja, J. W., Kuhar, M. J., Abraham, P., Burgess, J. P., Lewin A. H., Carroll, F.Y. J.Med. Chem. 1998, 41, 247. 3) Engelstoft, M.; Hansen, J. B. Acta Chem. Scand. 1996, 50, 164; Christensen, J. A.; Squires, F.R. US 4,007,196, 1977. 4) Navrátilová, H.; Potáček, M. Enantiomer, 2001, 6, 333. 4) March, J.; Advanced Organic Chemistry: Reactions, Mechanism, and Structures, 4th Ed., 1992, John Wiley and Sons, p. 582 and references therein. 6) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathé, D. J. Synth. Org. Chem. 1998, 1213; Saoudi, A.; Hamelin, J.; Benhaoua, H. Tetrahedron Lett., 1998, 39, 4035. 7) Kabalka G. W.; Pagni, R. M. Tetrahedron, 1997, 53, 7999.

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1. Pericyclic Reactions Initiated by Microwaves