Continuous Catalytic Oxidation in Pharmaceutical Processing B. Frank Gupton VCU John Monnier USC Steve Fong VCU Center for Rational Catalyst Synthesis Planning Grant Workshop University of South Carolina, Columbia, SC June 16, 2014

Project Title Research Team: Frank Gupton, John Monnier… Overview: Continuous Catalytic Oxidation in Pharmaceutical Processing Applications Technical Information: Coupling intelligent catalyst design with continuous process capabilities will provide an effective platform for the safe, selective and efficient oxidation of alcohols.

Industrial Relevance The ability to carry out the selective oxidation of highly functionalized molecules continues to be a major challenge in pharmaceutical process development. Issues:  Cost of Oxidizing Agents  Poor Atom Economy  Reaction Selectivity and Process Control  Product Purification  Extreme Reaction Conditions Examples: Swern Oxidation Tempo Oxidation

Goals of the Proposal Demonstrate the feasibility of flow reactor technology to carry out these types reactions using heterogeneous oxidation catalysts and O 2 as an oxidant. O2O2 Oxidation Catalyst 1 T1T1 Aldehydes from Alcohols Amides from Aldehydes and Amines O2O2 Oxidation Catalyst 1 Oxidation Catalyst 2 NH 2 R T1T1 T2T2 Amides from Alcohols and Amines NH 2 R O2O2 T2T2 Oxidation Catalyst 2

Proposed Hypothesis Coupling intelligent catalyst design with continuous process capabilities will provide an effective platform for the safe, selective and efficient oxidation of alcohols. Why Flow Chemistry: Heat transfer Mixing Reproducibility - Regulatory impact - Operational inefficiencies Safety -Short residence times - Small reactor volumes Chemistry - Kinetically controlled reactions Cost - Capital - Operational

Research Methods/ Techniques  Preparation of bimetallic oxidation catalysts by electroless deposition - Group 1B metals paired with Group VIII metals  Use continuous flow reactors to evaluate oxidation catalysts - Thales Nano X-Cube  Employ factorial design of experiments to evaluate critical process parameters - Reaction conditions - Throughput - Catalyst half life

Outcomes/ Deliverables  A continuous oxidation unit will be developed which will allow for the evaluation of the chemical diversity of oxidation reactions with a aromatic and aliphatic alcohols.  Establishment of optimal operating parameter by factorial design of experiments  Evaluation of preferred bimetallic catalyst system for oxidation under continuous operations  Results will be used to refine our computational model  Analytical methods will be developed to measure product quality in real time  Detailed kinetics for oxidation catalysts for catalyst optimization  Obtain detailed kinetics of oxidation reactions  Optimize catalyst synthesis methodology based on kinetic results

Impact Duration of Project and Proposed Budget  Demonstration of viability for continuous catalytic oxidation of aromatic and aliphatic alcohols with oxygen as an oxidizing agent  Reduction to practice of safe, cost effective and sustainable method for using oxygen as an oxidizing agent in organic synthesis  Optimization of bimetallic catalysts  Enhanced reaction performance under continuous flow conditions  Three Years  $60,000 Year 1 $60,000 Year 2