Selective Synthesis of a New Ascomycin Rearrangement Product (SDZ ASD732) on a Pilot Plant Scale

Abstract

The process for a pilot plant synthesis and the purification of a semisynthetic ascomycin derivative (1, SDZ ASD732) showing interesting biological activities is described. Conditions for the key transformation, a base-induced cascade of rearrangement and epimerization reactions of ascomycin leading to the selective formation of the new ascomycin derivative 1, were developed and successfully upscaled. Rapid screening of important reaction parameters was achieved by using automated parallel synthesis. In addition, a highly efficient purification process was found and implemented in the pilot plant process, resulting in an efficient separation of the semisynthetic ascomycin derivative from its by-products. The purification protocol consisted of preparative silica gel chromatography followed by a crystallisation step. Starting from crystalline ascomycin with a purity of ≥95%, an overall yield of 53% was achieved with a final purity of >98%.