A SCALABLE PROCESS FOR THE NOVEL ANTIDEPRESSANT ABT-200

A scalable process for the novel antidepressant ABT-200, starting with 5,6-methylenedioxy-1-tetralone, is described, The new process improve s the scale-up and safety concerns associated with the previously empl oyed route to ABT-200. The scalable process eliminates the potential f or HCN exposure to employees and produces ABT-200 in a stereospecific fashion. (TMS)CN was replaced by nitromethane as a reagent to introduc e the nitrogen in the ABT-200 molecule. This stereospecific process em ploys an epimerization procedure which takes advantage of a key differ ence in the solubility of the two diastereomers of the succinimide int ermediate, 9a/b and 10a/ b. Balancing the rate of epimerization with t he solubility of the diastereomers in the reaction medium was an essen tial 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 su ccinimide derivative 10a/b was then converted to ABT-200, This improve d procedure was used to prepare kilogram quantities of ABT-200.