Development of a Process for a Chiral Aminochroman Antidepressant: A Case Story†

The authentic development aiming at a full-scale method for the new chemical entity ebalzotan (code name NAE-086), a selective 5HT1A-agonist chosen as an Astra candidate drug primarily for the treatment of depression and anxiety is described. As it turned out, largely due to severe time constraints the original Medicinal Chemistry route of synthesis comprising 13 steps arranged in linear fashion (starting from 3-methoxyphenol) and including a “classical” diastereomer resolution to generate the desired (R)-enantiomer had to be scaled up without sufficiently developed methods at hand. This resulted in an extended batch cycle time of 5 months after which time a very poor overall yield of 0.25% (!) could be isolated, albeit the product showed excellent stereochemical purity of 99.9% (R). Starting from this deploring position a process was designed which proved to operate well in a 400−600 L pilot scale affording ∼27 kg of high quality material.