New production tools for current and future pharmaceuticals

1. New production tools for current and future pharmaceuticals Organic Reagents Gregory B. Dudley Assistant Professor Florida State University Aim 1: Bring a new product from the Dudley lab to the market Aim 2: Create a new market for a Dudley lab product line FSURF meeting February 14, 2008

2. What is an Organic Reagent? • A reagent is a “fine chemical” designed to achieve a specific chemical reaction • produced from petroleum commodity chemicals • market value of reagents exceeds $6 billion/year • Who buys organic reagents? • pharmaceutical industry ($600 billion/year in sales) • chemical research companies (Dow, DuPont, GE, etc.) • academic organic chemistry labs (ca. 1000 nationwide) • private research institutes (e.g., Scripps, Sloan–Kettering) • The Dudley lab reagents are tools for making drugs • benzyl reagent (on the market, Aim 1) • PMB reagent (market identified, Aim 1) • PSB reagents (new innovation, Aim 2)

3. Production tools for chemical synthesis: Specialized organic reagents • Problem: The increasing complexity of commercially relevant target molecules is outpacing the development of new organic synthesis technology • Result: Synthetic routes become longer, more elaborate, and more expensive • Solution: Develop specialized organic reagents

4. • similar or greater activity as compared to imidate • stable to storage • suitable for outsourcing • unsuitable for prolonged storage • prepared at Novartis (not outsourced) “all discodermolide… has been supplied by total synthesis” Specialized organic reagents in major commercial ventures: discodermolide (By this process, 100 kg/year of discodermolide would require more than 100,000 kg/year of PMB reagent) Process synthesis of discodermolide (Novartis):Org. Proc. Res. Dev.2004, 8, 92–130

5. Aim 1: Bring PMBO–L from the Dudley Lab to the market • Why: • Meet growing market demand for specialized organic reagents • Eliminate barriers to the use of Dudley lab technology: get this tool into the hands of the drug makers • How: • Demonstrate advantages of Dudley reagents over current technology • Benzyl–OPT (on market now) • PMBO–L (under development) • Develop manufacturing processes for preparing the PMBO–L reagent • Analyze costs / identify alternatives “The PMBO-lepidine protecting procedure worked great for us. Other conditions weren’t feasible for our substrate” – Prof Steve Castle, BYU

6. Aim 2: Create new markets for Dudley PSB technology • Why: • Unique market means no competition • Carbohydrate synthesis • Drug delivery polymers • Carbosilane materials • How: • Show the para-siletanylbenzyl (PSB) group doing things that nothing else can • Cleave using hydrogen peroxide (published) • Provide polymer support on demand • Collaborate on new carbosilane materials • Design a suitable PSB transfer reagent • Develop a PSB manufacturing process “if [a PSB reagent] were commercially available my research group would be ordering it” – anonymous peer review comment

7. laulimalide discodermolide eleutherobin Leading Taxol-like drug candidates • Microtubule-stabilizing agents • Active against Taxol-resistant tumors • In clinical / preclinical development • Each and every one prepared through synthesis using PMB technology

8. Acknowledgments • Contributing scientists • postdoctoral researchers • Hubert Lam, Kevin Poon, and Philip Albiniak • graduate students • Ernest Nwoye and Sami Fahd Tlais • undergraduate students • Jim Sunderhaus, Sarah House, and Cece O’Leary • Sigma–Aldrich Chemical Company • Nate Wallock • Florida State University GAP Committee • Jack Sams, Larry Lynch, Gus Ray, Eric McNair

9. New production tools for current and future pharmaceuticals Organic Reagents Gregory B. Dudley Assistant Professor Florida State University Aim 1: Bring a new product from the Dudley lab to the market Aim 2: Create a new market for a Dudley lab product line FSURF meeting February 14, 2008

10. GAP funding: activities to be completed within first year • Pave the way for new PMB reagent • Dudley benzyl and PMB technology surpass the capabilities of current methods • strong sales of current Dudley reagent (benzyl–OPT) will create a greater opening market for a PMB reagent • Market PMBO-L and/or PMBO-Q • lepidine-based PMBO-L is marketable but expensive • quinoline-based PMBO-Q would be more affordable • PMB and benzyl reagents impact major pharmaceutical discovery and manufacturing • Develop Dudley lab PSB reagents • create and control a new market

11. Aim 1a: Use benzyl–OPT to pave the way for PMB reagent • Why: • Benzyl–OPT is the “parent” or “prototype” • skilled practitioners will infer reactivity of PMBO-L based on benzyl–OPT studies • new applications will increase sales of benzyl–OPT • Brought to market on the strength of one synthetic application: • alcohol  alkyl benzyl ether (published) • “benzyl bromide and… benzyl 2,2,2-trichloro[acet]imidate failed. The best results were reached with 2-benzyloxy-1-methylpyridinium triflate” – Langlois et. al. • How: • Demonstrate advantages over current technology • phenol  aryl benzyl ether • carboxylic acid  benzyl ester (published) • thiol  alkyl benzyl sulfide • amine  benzyl amine • Demonstrate unparalleled, high impact reactivity • ketone  benzyl enol ether • self-quenching Friedel–Crafts reactions (published) • self-controlled Ritter reactions

12. Current manufacturing process for benzyl–OPT • Crude relative cost analysis of current routes • Sigma–Aldrich list prices • Bulk prices probably much lower in all cases Even at 25-times the price of the established product… “we have been very pleased with the year-to-date sales performance of this new product” – Dr. Nate Wallock, Sigma–Aldrich

13. Aim 1b: Develop synthetic route for the manufacturing of PMBO-L • Crude relative cost analysis of current routes • Sigma–Aldrich list prices • Bulk prices probably much lower in all cases

14. Aim 1b: Develop synthetic route for the manufacturing of PMBO-Q (new reagent?) • Prepare and examine alternative quinoline-based reagent • translate lepidine success into quinoline system • Compare quinoline- and lepidine- based reagents • chlorolepidine (original choice) cheaper than chloroquinoline • quinoline / oxidant combination would be ideal

15. Aim 2: Create new markets for Dudley PSB technology • Problem: Standard approach to OPT reagents incompatible with siletane • Progress: Modified approach successful, but requires expensive siletane • Solution: Combine siletane synthesis with PSB assembly into a one-step manufacturing process “if [a PSB reagent] were commercially available my research group would be ordering it” – anonymous peer review comment