Continuous Catalytic Oxidation in Pharmaceutical Processing

B. Frank GuptonVCU

John Monnier

USC

Steve FongVCU

Center for Rational Catalyst SynthesisPlanning Grant Workshop

University of South Carolina, Columbia, SCJune 16, 2014

Project TitleResearch 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 RelevanceThe 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 AgentsPoor Atom EconomyReaction Selectivity and Process ControlProduct PurificationExtreme Reaction Conditions

Examples:Swern Oxidation

Tempo Oxidation

H

HHO

HOCOCl2, DMSO

Et3N, CH2Cl2-780C

H

HOHC

OHC

1.5 eq. TEMPO

MeCN, 7 hr.

OH O

Goals of the Proposal

Demonstrate the feasibility of flow reactor technology to carry out these types reactions using heterogeneous oxidation catalysts and O2 as an oxidant.

OH

O2

CHOOxidation

Catalyst 1

T1

Aldehydes from Alcohols

Amides from Aldehydes and Amines

OH

O2

Oxidation

Catalyst 1

Oxidation

Catalyst 2

NH2R

T1 T2

Amides from Alcohols and Amines

O NHR

NH2R

O2

CHO

O NHR

T2Oxidation

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 BudgetDuration 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