The Princeton Section of the American Chemical Society
Presents
Synthesis on Scale:
Process Chemistry in the Pharmaceutical Industry
Friday, January 13th, 2023
10:00 AM – 2:45 PM EST
Remote via Zoom
Program
| 10:00 – 10:10 AM | Welcome and opening remarks Prof. Spencer Knapp, Rutgers University, Symposium Organizer, ACS Princeton Section |
| 10:10 – 11:00 AM | Duc N. Tran, Janssen Pharmaceutical “Process Development of Odalasvir;” Introduced by Sebastien Lemaire, J&J |
| 11:00 – 11:50 AM | Catherine Alder, GSK “Green Chemistry at GSK;” Introduced by Nicole Goodwin, GSK |
| 11:50 – 12:20 PM | Discussion (Duc, Catherine, Sebastien, and Nikki) |
| 12:20 – 12:40 PMs | (Break) |
| 12:40 – 1:30 PM | Branko Mitasev, Eisai “Crystallization-based syntheses of novel bicyclic azetidine antimalarials;” Introduced by Frank Fang, Eisai |
| 1:30 – 2:20 PM | Matthew Goldfogel, BMS “Transitioning from Palladium to Sustainable Nickel Catalysis for C-B and C-C Coupling Reactions;” Introduced by Hester Dang, BMS |
| 2:20 – 2:40 PM | Discussion (Brank, Matt, Frank, and Hester) |
| 2:40 – 2:45 PM | Closing remarks – Prof. Spencer Knapp |
Registration: Registration is free but required. Prior to the symposium, all who have registered will receive information on how to join the virtual platform. To register, please complete the form below. Note: Confirmation of your registration will appear on the screen.
A Tribute to Process Chemistry
Process development chemists are the unsung heroes of the pharmaceutical industry, working tirelessly to develop and optimize the manufacturing processes for life-saving medicines. Without their brilliant dedication, progress in drug discovery would grind to a halt. They are highly skilled and dedicated professionals who live to do chemistry and are committed to ensuring that the medications we rely on are produced with the highest level of quality and efficiency. Their hard work and dedication to their craft make a significant and positive impact on the lives of countless individuals around the world. Thank you to all the hard-working process development chemists for your tireless efforts in bringing much-needed therapies to patients in need. I stand in awe of your accomplishments and I am deeply honored and grateful to collaborate and interact with many of you.
Professor Phil Baran, Ph.D., Department of Chemistry | Scripps Research
Speaker Abstract and Biographies
Duc N. Tran, Research Project Lead, Chemical Process R&D, Janssen Pharmaceutical
Title: “Process Development of Odalasvir”
Abstract: Odalasvir is a selective inhibitor of NS5A protein, key target for combination therapies of hepatitis C virus. This presentation will highlight the chemical process development for the synthesis of this active pharmaceutical ingredient (API) featuring an imidazole ring formation, a Miyaura borylation and a double Suzuki coupling. Optimization of the reaction conditions, work-up, and isolations resulted in much higher throughput and signifincantly lower process mass intensity (PMI). This overall process is deemed robust for a commercial purpose and has been scaled up to 10-100 kg batches without major issues.
Biography: Duc Tran joined Janssen since 2015 and is currently a Research Project Lead in the Chemical Process R&D department. In this role, he acts as scientific leader in the design of commercial synthesis for small molecules, aligns API development plan with CMC strategy, develops and grows his team members. He is located in Beerse site, Belgium.
He started his chemistry studies with the Technical Degree from IUT Le Mans, France. He then moved to ENS de Chimie in Montpellier to finish his “diplome d’ingenieur” in organic chemistry. In 2014, he received his PhD from ETH Zurich under the guidance of Prof. Nicolai Cramer where he studied asymmetric C-H activation and total synthesis of Psiguadial family. He carried out his postdoctoral research at University of Cambridge with Prof. Steve Ley to learn and apply flow chemistry in generating and handling highly reactive species such as unstabilized diazo compounds.
Catherine M. Alder, Scientific Investigator, Medicinal Chemistry – Discovery High-Throughput Chemistry, GSK
Title: “Green Chemistry at GSK”
Abstract: A brief introduction to the GSK Green chemistry reagents and solvents guides followed by a case example utilising the tools that focusses on two routes towards the synthesis of cis or trans C2,3,5,7-tetrasubstitued dihydrobenzofurans as potent and selective BET BD2 inhibitors followed by the optimisation of the synthesis of the lead GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, an extensive optimisation of a fluorination step and a high yielding aminocarbonylation were key to generate the required 50 g of material.
Biography: Catherine graduated from the University of Sheffield, and joined GSK Stevenage in 2006, after a period at MSD. In 2016 Catherine was awarded her Chartered Chemist status by the RSC and has been an active STEM ambassador for the last 7 years. Since joining GSK she has worked in various Med chem groups. In 2012 she joined Green Chemistry, working on both in-house and external collaborations, such as the IMI:Chem21 project to improve the environmental impact of routes to APIs. While in Green Chemistry she worked closely with Med Chem to introduce changes earlier to ensure a longer term impact, and has looked for opportunities to try newer technologies such as flow chemistry, synthetic biochemistry, or working with atom efficient gases.
In 2020 Catherine was shortlisted in the TechWomen100 awards and in the same year she joined the Discovery High Throughput Chemistry department in Medicinal Chemistry – where she has further used screening and her optimisation skills in 96 well plates formats, reducing the amount of waste due to the scale, to identify better reaction conditions and profiles to deliver target compounds.
Development of GSK's reagent guides – embedding sustainability into reagent selection - Green Chemistry (RSC Publishing) Green Chem., 2013, 15, 1542-1549
Updating and further expanding GSK's solvent sustainability guide - Green Chemistry (RSC Publishing) Green Chem., 2016, 18, 3879-3890
Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow | Organic Process Research & Development (acs.org) Org. Process Res. Dev. 2022, 26, 2, 365–379
Branko Mitasev, Senior Principal Scientist, Precision Chemistry, Eisai, Cambridge MA
Title: “Crystallization-based syntheses of novel bicyclic azetidine antimalarials”
Abstract: The novel cPheRS inhibitor BRD5018 is being developed as a potential anti-malarial treatment through a collaboration between Eisai and The Broad Institute. The structurally complex bicyclic azetidine scaffold adorned with 5 stereogenic centers presents a substantial synthetic challenge particularly as the overall objective is to develop a cost-effective treatment for malaria. The previous route to BRD5018 included numerous chromatographic separations, a non-stereoselective dihydroxylation, and a low-yield late-stage Sonogashira reaction. Based on our previous experience developing cost-effective manufacturing routes to structurally complex natural product-based drug candidates at Eisai, a key aspect of the design criteria was to identify routes which had a high potential for including crystalline intermediates. Furthermore, carbohydrate-based routes (Chiron approach) would be attractive owing to the cheap source of chirality. This talk will present a new synthesis of BRD5018 that addresses all of these deficiencies and features: 1) A high yielding early stage Sonogashira reaction, 2) a highly diastereoselective glycine-ester Claisen rearrangement, 3) An efficient diastereomeric salt resolution, 4) a tandem aziridine ring-opening / azetidine ring-closure on an 2-amino-1,4-diol template to efficiently establish the all-cis trisubstituted azetidine scaffold with proper functionality for further derivatization, and 5) a low-cost 4-carbon synthon derived from D-ribose to afford a differentiated vicinal syn-diol suitable for a reductive amination/periodate cleavage/Staudinger-aza-Wittig sequence to form the 8-membered diazocene ring. Multiple crystalline intermediates enabled complete removal of chromatography from the synthesis and substantially reduced cost and waste generation, enhanced throughput and quality control.
Biography: Since joining Eisai in 2008, Branko has been involved in a variety of process research and medicinal chemistry projects. As a member of the process group, he developed and implemented synthetic routes to small molecule APIs to support pre-clinical and early clinical evaluation. In his current role, he leads an internal CNS discovery program. Branko is also involved in a number of external collaborations focused on Global Health.
Prior to his time at Eisai, Branko received his Bachelor of Science degree in Chemistry from Davis and Elkins College. In 2006, he earned a doctorate degree from the University of Pittsburgh in the labs of Prof. Kay Brummond working on transition metal catalyzed reaction of allenes. Subsequently, he conducted post-doctoral research in the labs of Prof. John Porco, Jr at Boston University, focusing on total synthesis of polyprenylated acylphloroglucinol natural products.
Matt Goldfogel, Scientific Investigator, Principal Scientist – Chemical Process Development, BMS
Title: “Transitioning from Palladium to Sustainable Nickel Catalysis for C-B and C-C Coupling Reactions”
Abstract: Designing an efficient, sustainable, and cost-effective syntheses of active pharmaceutical ingredients (APIs) is key to process chemistry. Palladium-catalyzed C-B and C-C bond forming reactions have become a ubiquitous tool in achieving this, but palladium catalysis requires a costly precious metal that is increasingly expensive to reliably source. Nickel-catalyzed borylation and Suzuki reactions are alternatives to palladium and have the advantages of improved scope for oxidative addition, facile metal purge, and abundant catalysts. These benefits compound when processes are scaled to generate kg of material, but are balanced by challenges such as unstable Ni(0) pre-catalysts, heterogeneous reaction conditions, and a perceived lack of reliability in coupling complex heterocyclic substrates. Our interest in nickel catalysis for process chemistry has led to the development of screening platforms for C-B and C-C bond formation to address process chemistry concerns, and a more reliable second-generation method that uses biphasic reaction conditions for nickel-Suzuki catalysis. This work is currently culminating in efforts to develop a direct telescope for nickel catalyzed borylation followed by Suzuki coupling to greatly improve process efficiency.
Biography: Matt Goldfogel has been part of the Chemical Process Development group at Bristol Myers Squibb since 2018 where he has worked on developing processes to make active pharmaceutical ingredients in oncology, cardiology, and hematology. One of Matt’s passions in process chemistry is incorporating base metals catalysis into commercial processes and he is particularly interested in using nickel catalysis to decrease the cost of medicines for patients. At BMS, Matt also participates in mentoring and training efforts alongside his role in recruiting new process chemists to the department. Feel free to reach out if process chemistry and pharmaceutical research is a passion you’d like to pursue!
Matt’s academic history began at Whitman College where he received a Bachelor of the Arts degree in Chemistry in 2011. He followed his interest in chemistry to the University of North Carolina at Chapel Hill where he was a founding member of the Meek Lab. There he studied carbodicarbenes ligands and their use with rhodium catalysts for alkene activation. Matt then pursued a postdoctoral position with Professor Dan Weix at the University of Rochester before moving with Professor Weix to the University of Wisconsin – Madison. In the Weix Lab he contributed to cross-electrophile coupling methodology and discovered his fascination with nickel as a base metal suitable for scaleup, green chemistry, and process development.
SOS Symposium Organizing Committee
Spencer Knapp, Rutgers University
Mukund Chorghade, Princeton ACS Section
David Carrick, Princeton ACS Section
Louise Lawter, Princeton ACS Section
Jennifer Albaneze-Walker, Bristol-Myers Squibb
Tariq Bhatti, Rutgers University, IT Support