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Issue 4, 2009
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Mechanistic studies on the synthesis of bicalutamide

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Abstract

Bicalutamide, a therapeutically important anti-androgen used in the treatment of hormone-sensitive cancers, may be synthesised from the appropriate halohydrin or epoxide. We report here studies aimed at demonstrating unambiguously that preparation of bicalutamide and its thioether analogue from the chlorohydrin under basic conditions proceeds via opening of an intermediate epoxide by the appropriate sulfinate or thiolate nucleophile, that the analogous anionic sulfur nucleophiles react under the same conditions and that the SN2 pathway involving direct displacement of chloride by the nucleophile does not operate. The proposed mechanism is confirmed by the quantitative fitting of sequential reaction kinetics, taking into account the competing dimerisation of the thiolate nucleophile that occurs under basic conditions. The O-methyl analogue of the chlorohydrin is unreactive towards thiolate under the same conditions, although a slower cyclisation to the β-lactam was observed. The implications of these observations for the analogous preparation of thioethers and sulfones are discussed.

Graphical abstract: Mechanistic studies on the synthesis of bicalutamide

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Publication details

The article was received on 11 Sep 2008, accepted on 10 Nov 2008 and first published on 24 Dec 2008


Article type: Paper
DOI: 10.1039/B815894K
Citation: Org. Biomol. Chem., 2009,7, 678-686
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    Mechanistic studies on the synthesis of bicalutamide

    N. Asaad and S. Fillery, Org. Biomol. Chem., 2009, 7, 678
    DOI: 10.1039/B815894K

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