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Synlett 2011(1): 57-60  
DOI: 10.1055/s-0030-1259085
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Chemoselective Staudinger Strategy in the Practical, Fit for Purpose, Gram-Scale Synthesis of an HCV RNA Polymerase Inhibitor

Louis-Charles Campeau*, Paul D. O’Shea
Department of Process Research, Merck Frosst Canada Ltd., 16711 Trans Canada Highway, Kirkland, Québec H9H 3L1, Canada
e-Mail: Louis-Charles_Campeau@merck.com;
Further Information

Publication History

Received 20 October 2010
Publication Date:
07 December 2010 (online)

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Abstract

The use of a late-stage selective Staudinger reaction in the preparation of the novel HCV RNA polymerase inhibitor is described.

Key words

Staudigner - nucleoside - 7-deaza-adenosine - azide - HCV NS5B

    References and Notes

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7

At higher temperatures, aromatic Finkelstein displacement of the Cl group was observed and elimination of the alkyl iodide proved sluggish requiring 2 d to proceed to 100% conversion. Increased heating resulted in decomposition of the sensitive vinyl ether product.

8

The beneficial effect of the large TBS protecting group on reactions at C4′ might result from a preferred conformation alignment. Further mechanistic investigation is ongoing and will be reported in due course.

14

Palladium-catalyzed hydrogenolysis and metal-mediated reductions (Zn, Mg, Fe) gave unsatisfactory results. Reduction with TMS2S resulted only in partial conversion.

18

Separation of the product from triphenylphosphine oxide was very tedious via traditional silica gel chromatography. With SCG-PPh3 a simple workup and precipitation procedure was devised: The reaction was concentrated and taken into CH2Cl2. This solution was then washed with sat. aq NaHCO3 and brine. The crude CH2Cl2 solution was then concentrated to a minimum amount of solvent required for complete solubilization. To this stirring solution was then added MTBE dropwise which resulted in precipitation of the SCG-phosphine oxide. The filtrate was concentrated to afford the reduced amine in >90% purity by HPLC.