Metathesis Applications in API Synthesis October 18th, 2016 2016 AGENDA Materia’s Catalyst Business Model Metathesis and Applications Maximizing Reaction Efficiency Macrocyclizations on Scale Capabilities, Services, and Support 2 MATERIA MATERIA’S BUSINESS MODEL 1. Catalyst Sales • IP included in purchase price • No license fees or royalties • No restrictions on patenting API composition or route • Transferable to 3rd party CMO/CRO 2. Technical Services • Process guidance (free) • Catalyst screening • Catalyst development • Process development and optimization • Intermediate synthesis (non-GMP) …our mission is to accelerate Grubbs’ catalyst use in the pharmaceutical industry MATERIA 3 Metathesis and Applications PRIMARY OLEFIN METATHESIS REACTIONS Ring-Closing Metathesis (RCM): makes ring structures Cross Metathesis (CM): creates new olefins (large or small molecules) Ring-Opening Metathesis Polymerization (ROMP): makes polymers Metathesis mechanism: Sanford, M. S.; Love, J. L.; Grubbs, R. H. J. Am. Chem. MATERIA Soc. 2001, 123, 6543. 5 POLYMER APPLICATIONS: ADVANCED MATERIALS Auto Composites • Developmental Lightweight Pressure Vessels • Developmental Electronic Materials • Developmental Subsea Insulation Subsea Buoyancy Chlorinated Fluid Handling • Commercial Downhole Tools • Commercial MATERIA 6 CHEMICAL APPLICATIONS: BIORENEWABLES 1-butene Olefins Metathesis Specialty Natural Grubbs Chemicals Oil Catalyst® Oleochemicals • Flexible feedstock process (palm, soy, rapeseed, canola, etc.) • Elevance was spun off as a JV between Cargill and Materia • Announced over 1.9 billion lbs+ / year of bio refinery capacity • Commercial-scale natural feedstock available for new product development and mass production using Grubbs Catalyst® based metathesis MATERIA 7 PHARMA APPLICATIONS: MACROCYCLES Ciluprevir Simeprevir HCV NS3-4A Protease Inhibitor HCV NS3-4A Protease Inhibitor Carbon-carbon bonds formed by olefin metathesis Horvath, A. et al (Janssen Pharmaceuticals, Inc., USA). Improved Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Yee, N. K.; Senanayake, C. H. Org. Proc. process for preparing an intermediate of the macrocyclic protease MATERIA Res. Dev. 2009, 13, 250. 8 inhibitor TMC 435. PCT Int. Appl. 2013061285, May 2, 2013. WHY MACROCYCLES? Potential to Hit “Undruggable” Targets • May replace larger molecules (e.g. biologics) for difficult targets1 • Large, saturated ring balances preorganization with flexibility2 Oral Bioavailabity Beyond Rule of 5 (bRo5) Space • Better diffusion across membranes in studies of matched acyclic/macrocyclic pairs (both peptide and non-peptide)3 • “Chameleon-like behavior” - exposed polar surface area in aqueous media, conformational changes (e.g. internal H-bonding) enable membrane permeability4 Unexplored Intellectual Property Space • Tying ends of pharmacophore into a macrocycle may lead to new, patentable composition 1. Espada, A.; Broughton, H.; Jones, S.; Chalmers, M. J.; Dodge, J. A. J. Med. Chem. General reviews: 2016, 59, 2255. Giordanetto, F.; Kihlberg, J. J. Med. Chem. 2014, 57, 278. 2. Mallinson, J.; Collins, I. Future Med. Chem. 2012, 4, 1409. Villar, E. A.; Beglov, D.; Chennamadhavuni, S.; Porco Jr., J. A.; Kozakov, D.; 3. Bogdan, A. R.; Davies, N. L.; James, K. Org. Biomol. Chem. 2011, 9, 7727. Vajda, S.; Whitty, A. Nature Chemical Biology, 2014, 10, 723. 4. Whitty, A.; Zhong, M.; Viarengo, L.; Beglov, D.; Hall, D. R.; Vajda, S. Drug Discovery MATERIA Today, 2016, 21, 712. 9 PHARMA APPLICATIONS: STAPLED PEPTIDES Small Stapled Drug Properties Biologics Peptides Metathesis-enabled peptide staples hold peptides Molecules Peptides in helical conformation to enhance stability and Cell Penetration ++ -- -- ++ cell penetration while maintaining specificity. Specificity + ++ ++ ++ Stability ++ ++ -- ++ 1. Drahl, C. C&E News vol. 86, no. 22. pp.18-23 (June 2, 2008). 2. http://aileronrx.com/science_stapled-peptide-technology.php MATERIA 3. Image: Kim, Y.-W.; Grossman, T. N.; Verdine, G. L. Nature Protocols 2011, 6, 761. 10 PHARMA APPLICATIONS: OTHER SP3-RICH STRUCTURES Saturated N-Heterocyclic Spirocyclic NK-1 Cathepsin K Inhibitor Receptor Antagonist Carbon-carbon bonds formed by olefin metathesis Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J. Sprague, V. Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M. Jr. Org. M.; Castellanos, L. P.; Chen, Y.; Piorier, M.; Mergelsberg, I. (Schering- MATERIA Process Res. Dev. 2008, 12, 226. 11 Plough, USA) WO2010028232, 2010 Maximizing Reaction Efficiency CATALYST SELECTION General RCM General CM C848 C627 C949 Grubbs II Hoveyda-Grubbs II Nolan-Grubbs II RCM to Trisubstituted CM to Trisubstituted Z-selective (CM or RCM) C571 C711 C633 MATERIA 13 GENERAL PURPOSE CATALYSTS IN ACTION Ring-Closing Metathesis1,2 C627 Hoveyda-Grubbs II Cross Metathesis3 C848 Grubbs II 1. Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M. Jr. Org. Proc. Res. Dev. 2008, 12, 226. 2. Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M. Jr. Tetrahedron 2009, 65, 6291. MATERIA 3. Wang, G.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 8088. 14 STERIC SPECIALIST CATALYSTS IN ACTION Ring-Closing Metathesis1 C823 (Grubbs I): 0% C627 (Hoveyda-Grubbs II): 0% C571 C571: 82% Cross Metathesis2 C571: 60% C627 (Hoveyda-Grubbs II): 78% C711 C711: 98% 1. Allen, C. E.; Chow, C. L.; Caldwell, J. J.; Westwood, I. M.; van Montfort, R. L. M.; Collins, I. Bioorg. Med. Chem. 2013, 21, 5707 MATERIA 2. Stewart, I. C.; Douglas, C. D.; Grubbs, R. H. Org. Lett. 2008, 10, 441. 15 Z-SELECTIVE CATALYST IN ACTION Ring-Closing Metathesis1 2 Cross Metathesis C633 1. Mangold, S. L.; Grubbs, R. H. Chem. Sci. 2015, 6, 4561. 2. Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem. MATERIA Int. Ed. 2013, 52, 310. 16 TEMPERATURE AND CONCENTRATION Ring-Closing Metathesis Heat Necessary? Temperature (°C) Concentration (M) No, unless there is ring strain No, unless there is ring strain Possibly, if there is an entropic barrier Yes, entropic barrier and high dilution are likely Yes, to overcome sterics MATERIA 17 TEMPERATURE AND CONCENTRATION Cross Metathesis Heat Necessary? Temperature (°C) Concentration (M) No, Type I CM is fast Yes, electron deficient olefins are slow to react Yes, to overcome sterics No, selectivity may suffer at higher temperature MATERIA 18 SOLVENT SELECTION Preferred Solvents Tolerated Solvents Avoid if Possible (non-coordinating) (coordinating/nucleophilic) (strongly coordinating) hexane, heptane MeOH, EtOH, i-PrOH MeCN toluene, xylene Acetone, HOAc DMSO, DMF, NMP TBME, 2-MeTHF Et2O, THF Pyridine and other amines DCM, DCE, PhCl water (neutral/acidic) water (basic) EtOAc, i-PrOAc Perfluoroalkanes http://allthingsmetathesis.com/solvent-considerations-in-ruthenium-catalyzed-metathesis-reactions MATERIA 19 WATCH FOR SOLVENT IMPURITIES . Inconsistent results on scale-up − Catalyst deactivation − Olefin isomerization − Epimerization of vinylcyclopropane . Identified morpholine as an impurity in toluene (<20 ppm) − [morpholine] ~ [catalyst] . Purification of toluene led to consistent results MATERIA Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9, 513. 20 COORDINATING GROUPS: ADD ACID Potential ligands Catalyst (10 mol%) Additive, Time Yield (trans:cis) C823 (Grubbs I) None, 16h n.d. C848 (Grubbs II) None, 16h n.d. C823 (Grubbs I) 5 equiv HCl in MeOH, 16h 10 %, 86:14 C848 (Grubbs II) 5 equiv HCl in MeOH, 4h 70 %, 94:6 C823 (Grubbs I) 5 equiv TFA in MeOH, 16h 8 %, 85:15 C848 (Grubbs II) 5 equiv TFA in MeOH, 4h 86 %, 94:6 MATERIA William, A. D.; Lee, A. C.-H. Chimia, 2015, 69, 142. 21 COORDINATING GROUPS: START WITH THE SALT Varubi®(rolapitant) FDA-approved September 2015 for treatment of chemotherapy-induced nausea and vomiting) Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J. Sprague, V. M.; Castellanos, L. P.; Chen, Y.; Piorier, M.; Mergelsberg, I. (Schering-Plough, USA) MATERIA WO 2010028232, March 11, 2010 22 OLEFIN ISOMERIZATION Vaniprevir RCM Kong, J.; Chen, C-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, MATERIA J.; Li, H.; Zacuto, M. J. J. Org. Chem. 2012, 77, 3820. 23 OLEFIN ISOMERIZATION - HYPOTHESES Hydride Formation Nanoparticles 1. http://allthingsmetathesis.com/inhibiting-olefin-isomerization/ 2. Ru-H formation: Dinger, M. B. Mol, J. C. Eur. J. Inorg. Chem. 2003, 15, 2827. 3. Ru-H isomerization (in)activity: Higman, C. S.; Plais, L.; Fogg, D. E. ChemCatChem 2013, 5, 3548. 4. RuNPs: Higman, C. S.; Lanterna, A. E.; Marin, M. L.; Sciano, J. C.; Fogg, D. E. MATERIA ChemCatChem 2016, 8, 2426. 24 OLEFIN ISOMERIZATION - PREVENTION C848 Grubbs II Additive Equiv A B none - <5% >95% AcOH 0.1 >95% none benzoquinone 0.1 >95% none galvinoxyl 0.2 80% 20% TEMPO 0.5 7% 93% 4-methoxyphenol 0.5 17% 83% BHT 0.5 4% 93% Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, MATERIA 127, 17160. 25 CATALYST STABILITY - INERT CONDITIONS Decomposition of C627, C848, C827, & C949 • Catalyst solutions were prepared 100 with rigorous exclusion of oxygen C627 and moisture (samples were 90 % C627 (C6D6) prepared in the glovebox using % C627 (CD2Cl2) 80 C949 freshly distilled and/or degassed % C627 (CDCl3) NMR solvent). 70 % C627 (C6D6 wet) C827 % C827 (C6D6) 60 • 0.02 M catalyst in NMR solvent % C827 (CD2Cl2) C848 % C827 (CDCl3) with internal standard 50 % C827 (C6D6 wet) % C848 (C6D6) • Wet Benzene contained 0.035 M 40 catalyst remaining (%) remaining catalyst % C848 (CD2Cl2) H O1 2 30 % C848 (CDCl3) % C848 (C6D6 wet) 20 • NMR samples were stored on % C949 (C6D6) bench top at room temp in the % C949 (CD2Cl2) 10 dark over the 8 days. % C949 (CDCl3) 0 % C949 (C6D6 wet) 0 20 40 60 80 100 120 140 160 180 200 time (h) Adam Johns MATERIA 26 CATALYST STABILITY - NON-INERT CONDITIONS Decomposition of C627, C827, C848 & C949 (Air) • Catalyst solutions were prepared 100 by sparging with oxygen, no C627 attempt to keep moisture out of 90 % C627 (C6D6) % C627 (CD2Cl2) the samples. (Samples were 80 prepared outside of the glovebox, % C627 (CDCl3) on the lab bench top with NMR 70 % C627 (C6D6 wet) solvents used as is).