Environmentally friendly racemization process for the benzofuroquinolizines : A process for the racemization of T1143 for waste-stream recovery

Abstract

Control of racemization and chirality are of high importance in chemistry of active pharmaceutical ingredients (APIs), in terms of drug design, development and production. Even though it is desired to develop and produce de novo enantiopure compounds, certain syntheses cannot be achieved to yield enantiopure end-products. Thus, mastering the racemization techniques is of great importance to be able to recover the product from its stereoisomer in the process where enantiopure synthesis cannot be achieved. At the same time, financial burden and the environmental impact of the synthetic process should be managed. Herein, a novel and environmentally friendly method for racemizing a commercially available veterinary active pharmaceutical ingredient (VAPI) intermediate, named T1143, is introduced. T1143 is a small molecule containing a tertiary nitrogen, a ketone group, and a stereogenic center of interest at -position to the ketone group. Racemization of this VAPI intermediate has been studied by various methods to recover the loss of half of the desired product, (S)-T1143, during production and purification. (R)-T1143, the undesired enantiomer, is collected from the waste stream, and converted into (S)-T1143 through formation of aza-retro-Michael/aza-Michael equilibrium by refluxing it at certain concentrations in aqueous solutions. This equilibrium mechanism leads to the racemization of benzofuroquinolizine-ones where the (R)-enantiomer can be converted into a racemic mixture, (RS)-T1143, in an efficient and environmentally friendly manner. The resolution of (RS)-T1143 is achieved by converting it to the (-)–O, O’- Di-p-toluoyl-L-tartaric acid (DTTA) salt, which can be crystallized in the presence of the corresponding (S)-T1143 salt.