WEDNESDAY, OCTOBER 17

8:45 am Chairperson’s Remarks

8:50 Biocatalysis in Process Research
Paul N. Devine, Ph.D., Associate Director, Process Research, Merck & Co., Inc.
Investigative pharmaceutical agents typically contain multiple functional groups and one or more stereocenters and must be isolated in high chiral as well as chemical purity. Methods such as classical resolution and chiral chromatography can be useful in the synthesis and purification of these drug candidates but have drawbacks. For example resolutions often suffer from low overall yield and normally require either acidic or basic functionalities while chiral chromatography is typically solvent and time intensive. For these reasons a selective synthesis to prepare the desired functionalities with high chemo, enantio, and/or diastereo control is greatly desirable. Biocatalytic agents play an increasing role in the design and execution of these selective syntheses due to the high chemo and stereoselectivity exhibited by these biocatalysts. The coupling of commercially available enzymes with rapid screening technologies allows for the useful generation of “hits.” Further process development involving the careful study and control of reaction parameters such as temperatures, solvent ratios, or rates of additions can then provide the desired synthetic intermediates in both high yield and high optical purity. Recent successes from our laboratories will be discussed.

9:20 Green Manufacture of Chiral Alcohols Using Custom-Evolved Biocatalysts – Replacing Boron-Based Reducing Agents
Chris Davis, D.Phil., Associate Director, Analytical Biochemistry, Codexis, Inc.
Chiral secondary alcohols are prominent intermediates in syntheses of chiral active pharmaceutical ingredients (APIs). They are commonly produced from the corresponding ketones using boron-based reducing agents, which are hazardous and often require cryogenic conditions to achieve acceptable stereopurity. Using its advanced directed evolution technologies, Codexis has evolved highly active and stereoselective ketoreductases, enabling the development of scaleable, economically advantageous, green biocatalytic process reactions for manufacturing chiral alcohol intermediates. The application of these catalysts for the synthesis of intermediates in the manufacture of atorvastatin (API in Lipitor®), ezetimibe (API in Zetia® and Vytorin®), and montelukast (API in Singulair®) will be shown.

9:50 Biocatalysis for Green Chemistry and Chemical Process Development 
Junhua Tao, Ph.D., Chief Scientific Officer, BioVerdant
Biocatalysis is becoming a transformational technology for green chemistry and chemical process development as a result of recent advances in large-scale DNA sequencing, structural biology, protein expression, high-throughput screening, directed enzyme evolution, and pathway engineering. In this presentation, some recent applications of biocatalysis will be described to illustrate an integrated approach to developing efficient green chemistry processes for the production of active pharmaceutical ingredients.

10:20 Networking Coffee Break

10:50 Technology Watch (Sponsorship Available)

11:05 Moderated Panel Discussion: Toward Greener API Manufacturing 

• Strategies for Greener Synthesis 
• Measuring Green Chemistry Performance 
• Challenges for Sustainable Chemistry 
• Drivers (e.g., environmental, economic, safety) 
• Corporate Initiatives 
• Opportunities for Industrial Cross-Fertilization 
• Stocking the Toolbox

12:05 pm Lunch on Your Own or Luncheon Technology Workshops
(Sponsorships Available)

1:35 Green Chemistry: Process Improvements through Mechanistic Design 
John C. Warner, Ph.D., Director, Center for Green Chemistry & Professor, Plastics Engineering, University of Massachusetts Lowell
The field of green chemistry has been expanding in the past few years. Its interdisciplinary nature has allowed for the “cross fertilization” of innovations across various industry sectors. This presentation will describe a number of emerging technologies and chemical transformations that illustrate various opportunities within pharmaceutical design and synthesis. 

2:05 Greener Chemical Synthetic Approaches to Heterocycles, Noble Nanometals, and Nanocomposites
Rajender S. Varma, Ph.D., Senior Scientist, U.S. Environmental Protection Agency, National Risk Management Research Laboratory Sustainable Technology Division
An efficient and sustainable approach to rapid organic synthesis using “greener” conditions, especially in the context of multi-component condensation reactions that are amenable to building libraries of compounds, is described. The use of solvent-free mechanochemical mixing, or microwave activation under a variety of benign reaction conditions such as neat reactants or solid-supported catalysts, safer solvents (water, polyethylene glycol) is summarized to expeditiously assemble a diverse array of useful target molecules. Similar strategy for the generation of metallic or bimetallic nanomaterials in eco-friendly medium or in crosslinked form as nanocomposites will be presented, which may find useful application in chemical synthesis.

2:35 A Mild Version of Grignard Reagents and Its Application for the Production of Drug Substances
Xiao-jun Wang, Ph.D., Senior Principal Scientist, Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc.
The interaction between Grignard reagents with bis[2-(N,N dimethylamino)ethyl] ether and other diamino ligands modifies the reactivity of Grignard reagents. As a result, addition of these Grignard reagents to acyl chlorides provides aromatic ketones selectively. In addition, it allows a mild halogen/magnesium exchange of aromatic halides bearing sensitive functional groups under non-cryogenic conditions.

3:05 Process Research on the Halichondrin B Analog Eribulin Mesylate: A New Route to C.14-C.26
Charles E. Chase, Ph.D., Senior Scientist, Process Research, Eisai Research Institute

3:35 Questions and Answers 

4:00 Close of Conference