Pharmaceutical Industrial Experiments on Continuous Cryogenic Reactions Using Mini-Sized Multi-Stage Reactors

Abstract

The pharmaceutical industry frequently uses cryogenic conditions for organometallic reactions and for the stereoselective synthesis of active pharmaceutical ingredients. Cryogenic conditions are required for these reactions either because of the thermal instability of the organometallic compound, or in order to improve the selectivity of the reaction. This paper focuses on continuous cryogenic organic reactions using mini-sized multi-stage reactors with volumes ranging from 10–6 to 10–3 m3. Mini-sized reactors have many advantages, such as high heat exchange, and efficient and fast mixing comparable to micro-scale reactors. However, mini-sized reactors are easier to operate than micro-scale reactors. The present study deals with synthesis of spirolactone fragment of neuropeptide Y receptor antagonist which is a potential anti-obesity agent. Currently, production is carried out in a semi-batch manner. Due to limitations in heat transfer, temperature control is maintained by slow addition of reactants, although this leads to poor product yield, especially in the second step of the process. The present results, obtained using a mini-sized multi-stage reactor, are compared with the current production scale approach in terms of the product yield, the amount of by-products and the stereoselectivity of the product.