不斉有機触媒を用いる神経障害性疼痛薬ミロガバリンの高効率的合成法の開発

Mirogabalin besilate is an α2δ ligand that is developed by Daiichi Sankyo as a drug for the treatment of neuropathic pain. This compound has an intricate and highly strained bicyclo[3.2.0]-heptane skeleton having three consecutive asymmetric centers on the ring, and therefore, it presents formidable synthetic challenges. In this study, we present a highly efficient manufacturing process for mirogabalin, employing an organocatalytic kinetic resolution of a racemic bicyclic ketone as a key step. This synthesis commences with the efficient construction of the racemic ketone via Claisen rearrangement and intramolecular [2+2] cycloaddition, using readily available butyraldehyde as the starting material. Subsequently, the racemic ketone was subjected to the kinetic resolution through an aldol reaction with p-formylbenzoic acid in the presence of an asymmetric organocatalyst. This reaction is designed so that the desired enantiomer can be easily purified and isolated with a high enantiomeric purity from the crude product by simple liquid-liquid separation and distillation. Finally, an efficient process from the optically active ketone to mirogabalin besilate is also developed, relying on Ti-mediated Knoevenagel condensation, highly diastereoselective cyanation to construct the quaternary asymmetric center, and cascade reaction of semi-hydrolysis and decarboxylation. This newly developed process provides mirogabalin besilate in good yield and high purity in an efficient and inexpensive manner. Consequently, this process has been routinely utilized for the production of this drug at industrial scale, representing one of the pioneering examples where an asymmetric organocatalytic reaction is utilized for pharmaceutical production.