A scalable process for the synthesis of the Bcl inhibitor obatoclax
Recently we created the novel indolylprodigiosin derivative 2 (obatodax) and demonstrated its ability to antagonize multiple members of the B-cell lymphoma (Bd) family of antiapoptotic proteins. The compound has shown potent anticancer activity in several animal tumor models. Obatodax is now in Phase 1b and 2 clinical trials directed against multiple hematologic and solid tumor malignancies. To support its clinical development, a new scalable synthesis was required. Obatodax has been prepared using a three-step synthesis, starting from commercially available 4-methoxy-3-pyrrolin-2-one. The reaction sequence involves a haloformylation reaction followed by a Suzuki cross-coupling reaction with an indole-2-boronic add. The synthesis is completed by an acid-mediated condensation with 2,4-dimethyl-1H-pyrrole.
Trisoxazoline/Cu(II)-catalyzed asymmetric intramolecular Friedel-Crafts alkylation reaction of indoles
Intramolecular Friedel-Crafts alkylation reaction of indoles catalyzed by trisoxazoline/copper(II) is described. This annulation provides an easy access to polycyclic indole derivatives with up to 90% ee in up to 99% yield.