A Scalable Process for the Novel Antidepressant ABT-200

Abstract

A scalable process for the novel antidepressant ABT-200, starting with 5,6-methylenedioxy-1-tetralone, is described. The new process improves the scale-up and safety concerns associated with the previously employed route to ABT-200. The scalable process eliminates the potential for HCN exposure to employees and produces ABT-200 in a stereospecific fashion. (TMS)CN was replaced by nitromethane as a reagent to introduce the nitrogen in the ABT-200 molecule. This stereospecific process employs an epimerization procedure which takes advantage of a key difference in the solubility of the two diastereomers of the succinimide intermediate, 9a/b and 10a/b. Balancing the rate of epimerization with the solubility of the diastereomers in the reaction medium was an essential factor in optimizing the yield and efficiency of this simple, one-pot reaction. The solubility-directed epimerization was demonstrated in both a predominantly aqueous and an organic solvent mixture. The succinimide derivative 10a/b was then converted to ABT-200. This improved procedure was used to prepare kilogram quantities of ABT-200.