Lab-Scale Preparation of a Novel Cyclopenta[b]furan Chemokine Receptor Antagonist

The preparation of a chemokine receptor type 2 (CCR-2) antagonist bearing a cyclopenta[b]furan core is described on a 600 g scale. Compared to our previously reported synthesis of the all-carbon core CCR-2 antagonist with a similar peripheral 3-methoxypyran appendage, our work required a redesign of the original Discovery Chemistry route and took advantage of a side product seen in the diastereoselective alkylation reaction. Elaboration by reduction and oxy-cyclization eventually led to the required N-Boc acid method. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents such as selenium and chromium that would not be used in a large-scale process setting, the overall route went through intermediates that could certainly be used for future scale-up campaigns. The synthesis provided a method to make lab-scale quantities of the final succinate salt to support tox/toleration studies. Relative to the Discovery Chemistry route, this lab-scale route featured novel intermediates that could open new avenues for future research in this area.