MONDAY, OCTOBER 15

7:30 am Pre-Conference Short Course Registration

8:30 Welcome by Short Course Instructor

8:40 Currents of Green Chemistry Underlying Cost-Effective Process Development
Since green chemistry approaches can markedly decrease the cost of goods (COG), corporations are applying these approaches more often: 

• Selecting green solvents and catalytic reagents that minimize waste byproducts
• When the “greenest” reagents might not be chosen
• Simple workups that minimize waste streams and optimize solvent recovery and reuse
• Direct isolation guidelines
• Process intensification.

9:20 Route Selection Goals
By designing a cost-effective route early in the development of a clinical candidate, the cost of development may be markedly decreased in Phase II and perhaps earlier. 

• Identifying commercially available starting materials
• Incorporating crystalline intermediates
• Exploiting enzymes for stereoselective processes
• Recognizing opportunities for CIDR (crystallization-induced dynamic resolution) and CIAT (crystallization-induced asymmetric transformation) processes
• Best location of convergent steps.

10:00 Optimizing Process Development by Minimizing Impurities
Although the initial goal of process optimization is to increase the yield by minimizing impurity formation, the quest to minimize and control impurities drives process development. 

• Controlling reaction conditions is necessary to guide optimization
• Biasing in-process assays in favor of the impurities 
• Recognizing opportunities for continuous processes 
• Decreasing the purification burden by decreasing the charge of a metal catalyst, which unfortunately increases the negative impact of inhibitors 
• Techniques to remove metal salts from the API
• Anticipating and avoiding or minimizing genotoxins in the API, and preparing tox batches of suitably high impurity levels.

10:40 Networking Coffee Break 

11:10 Developing Selective Crystallizations
Selecting and reproducibly preparing the optimal final form (salt, polymorph, and solvate) is a crucial aspect of thorough process development. 

• Gradually applying crystallization pressure 
• Designing crystallizations to dissolve impurities 
• Exploiting polymorphs and solvates for reliable processing of intermediates 
• More recent crystallization techniques including sonochemical crystallization. 

11:50 Process Refinements
Often there is little time to refine a process before scale-up, but such experiments can avoid scale-up difficulties with relatively little additional effort. 

• Use-tests, abuse tests, and process tolerance tests 
• Mass balances 
• The importance of water 
• Detailed examinations can lead to optimization within filed guidelines 
• Assessing simplicity and ruggedness.

12:30pm Close of Pre-Conference Short Course
Separate Registration Required for Pre-Conference Short Course

12:30 Main Conference Registration 

1:30 Chairperson’s Welcoming Remarks

1:40 Process Development and Scale-Up of AG035029, a Potent PPARg Agonist for Treatment of Type II Diabetes
Shu Yu, Ph.D., Associate Research Fellow, Research-API, Pfizer Global R&D-Groton
A practical process for the synthesis of PPARg agonist AG035029 was developed that involves six steps along the longest linear path. The process development utilized automated technology and computational chemistry extensively to accelerate the speed of the project in the areas of catalyst screening, reaction optimization, mechanistic studies, and polymorph control. The technologies employed in the process development included: high pressure automated reactors, in situ IR spectroscopy, a miniature computer-controlled multiple reactor system, and real-time FBRM monitoring.

2:10 Practical Synthesis of TRPV1 Antagonists for Treatment of Pain
Oliver Thiel, Ph.D., Senior Scientist, Chemical Process R&D, Amgen, Inc.
The synthesis and development of the clinical candidates AMG 517 and AMG 628, two potent TRPV1 antagonists, will be described. Both approaches benefited from the development of a highly selective etherification step of 4,6-dichloropyrimidine with the 4-hydroxy-2-acetamidobenzothiazole. Subsequent Suzuki coupling or amination, respectively, afforded the drug candidates. Practical preparations of the benzothiazole from anisidine through the Hugerschoff procedure and an improved piperazine synthesis will also be presented. 

2:40 Catalytic, Enantioselective Synthesis of Taranabant, a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist for the Treatment of Obesity 
Cheng-yi Chen, Ph.D., Distinguished Senior Investigator, Department of Process Research, Merck Research Laboratories
Chiral amide (MK-0364, taranabant) is a potent, selective, and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity. An asymmetric synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol is disclosed. Conversion of the alcohol intermediate to the chiral amide (MK-0364, taranabant) is accomplished in good overall yield.

3:10 Networking Refreshment Break, Poster and Exhibit Viewing

3:40 Identification and Development of Efficient Process Methodology: Case Studies on Selective Monoamine Reuptake Inhibitors 
Roger P. Bakale, Ph.D., Executive Director, Process R&D, Sepracor, Inc.
Among the myriad of important structural motifs in the pharmaceutical industry providing interesting CNS pharmacological activity, selective monoamine reuptake inhibitors specifically targeting serotonin, norepinephrine, and dopamine remain a central focus in the discovery and development of new target molecules. Of the “privileged core structures” common in the pharmaceutical industry for CNS indications, the tetrahydronaphthalenes, arylcycloalkyl amines, and piperidines are particularly noteworthy structural cores. The synthetic methodology and strategies utilized in large-scale preparation of targets containing these core structures will be disclosed. This presentation will highlight these synthetic strategies and provide specific process case studies of some of the selective monoamine reuptake inhibitors under development at Sepracor Inc.

4:10 From First Bulk to a Commercial Route: Evolution of the Torcetrapib Process
Matt Weekly, Senior Scientist, Development API, Pfizer, Inc.
Torcetrapib is a potent, selective CETP inhibitor developed as a combination with atorvastatin to raise HDL and lower LDL and total cholesterol. The torcetrapib-atorvastatin combination therapy was projected to require approximately 300 metric tonnes of torcetrapib annually. Due to the high projected volumes, it was immediately apparent that an efficient, environmentally friendly process was highly desirable prior to full-scale manufacturing. Through the course of our process development activities, significant changes were made to improve the synthesis of torcetrapib for operability and quality as well as to minimize environmental impact. The green chemistry principles were employed to aid in design and selection of the preferred route, its optimization, and subsequent scale-up. As a result, a more efficient and environmentally friendly manufacturing process was developed. 

4:40 Questions and Answers 

5:00 Networking Reception in the Exhibit Hall

6:30 Close of Day One