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

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.