We describe the synthesis, chromatographic purification, and isolation of the epothiloneÀfolic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10À30 g) of cGMP quality BMS-753493.
We report evidence for a strongly geometry-dependent substituent effect. The rate constants for H-D exchange of the R-hydrogens, (k exch ) OR , in a set of 19 β-alkoxy sulfones of known, fixed (or strongly preferred) H-C R -C β -OR torsion angles have been measured. Those of corresponding model compounds lacking the alkoxy group, (k exch ) model , were also measured, thereby providing the ratio, k N ) (k exch ) OR /(k exch ) model ; the k N values so obtained range over more than 4 orders of magnitude. We show that when due allowance is made for steric and other influences, our observations are consistent with an equation of the form log k N ) a + b cos 2 θ (where a ) 1.70 ( 0.17 and b ) 2.62 ( 0.20). It is further shown that the observed rate constant ratios are not consistent with a substituent effect consisting only of the inductive effect and the field effect, and that they are fully consonant with the additional presence of a third effect, namely negative hyperconjugation or the generalized anomeric effect, specifically a torsion-angle-dependent donation of the partial negative charge of the incipient carbanion into the σ C-O / orbital. This effect is largest with torsion angles of 0 and 180°and at these torsion angles constitutes the major source of stabilization of the incipient carbanion by the β-alkoxy group. The present observation of a torsion-angle-dependent substituent effect may be combined with the known adherence of the specific rate of R-sulfonyl carbanion formation to the Taft equation, to provide an equation yielding torsion-angle-dependent Taft σ* constants for the alkoxy group: (σ θ / ) OR ) 0.35 + 0.55 cos 2 θ. The idea of torsion angle dependence is usefully applied to the long-standing problem of the mechanisms of base-promoted elimination with 2-tosyloxycyclohexyl p-tolyl sulfones.
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