Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589)

( R )-Troloxamide quinone (EPI-589) is a compound that is under development as a therapeutic agent for Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The compound is derived from Trolox, a vitamin E derivative, using optical resolution and subsequent chemical conversion processes to obtain the active pharmaceutical ingredient (API). However, in the initially developed manufacturing method, pseudoephedrine was used as the optical resolution reagent, although it is restricted for use as a stimulant drug raw material in several countries, and the reproducibility of the optical resolution was not high. Thus, it was necessary to find an alternative chiral amine, which would be more freely usable and give high reproducibility. Among several optical resolution conditions investigated, an unusual three-component complex between ( R )-Trolox, ( R )-phenylethylamine, and N -methyl-2-pyrrolidone (NMP) was identified as most effective. However, although the optical resolution process showed both high reproducibility and optical purity, the manufacturing method came with the risk of introducing nitrosamines into the active pharmaceutical ingredient, so further extensive investigations were conducted to address this issue. As a result, a flow chemistry process was developed, which could avoid the use of a nitrate reagent in the oxidation step, and thus eliminate the risk of nitrosamine generation. This paper discloses the process development studies and discusses the successful manufacturing of EPI-589 on a scale of several hundred kilograms, utilizing the novel optical resolution and flow chemistry process under GMP conditions.