(105a) Development of a Multistep Continuous Process and Manufacturing for a Key Pharmaceutical Intermediate of Dapagliflozin

Wang, C., Bristol-Myers Squibb Co.
Deshpande, P., Bristol-Myers Squibb Company
Fan, J., Bristol-Myers Squibb Company
Lehmann, L., Bristol-Myers Squibb Company

While conventional batch possessing dominates most API-related pharmaceutical manufacturing operations, continuous processing technology has been attracting increased attention due to  its inherent benefits such as enhanced mass and heat transfer, precisely-controlled reaction times, and the use of small reactors.  In the synthesis of Dapagliflozin, the preparation of a key pharmaceutical intermediate, BMS-587319, by common batch processing requires cryogenic conditions to ensure acceptable stability and yield of certain reactive species.  To overcome potential challenges for scale-up on cryogenics requirement and process efficiency, a continuous process was later developed and demonstrated successfully on scale to convert the low-temperature synthesis to an energy-efficient, non-cryogenic operation.  In addition to these manufacturing advantages, the continuous flow production consistently delivered comparable product quality and yield to the batch process over multiple campaigns.  In this presentation, laboratory development, scale-up and production of BMS-587319 by continuous processing will be discussed.