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). % C827 (C6D6) 60 % C827 (CD2Cl2) C949 % C827 (CDCl3) • 0.02 M catalyst in NMR solvent 50 with internal standard % C827 (C6D6 wet) 40 % C848 (C6D6)
catalyst remaining (%) remaining catalyst % C848 (CD2Cl2) Wet Benzene contained 0.035 M • 30 C827 % C848 (CDCl3) H O1 2 % C848 (C6D6 wet) 20 % C949 (C6D6) • NMR samples were stored on % C949 (CD2Cl2) 10 C848 bench top at room temp in the % C949 (CDCl3) dark over the 8 days. 0 % C949 (C6D6 wet) 0 20 40 60 80 100 120 140 160 180 time (h) Adam Johns MATERIA 27 EXCLUDING OXYGEN AND OXIDANTS
. O2 and hydroperoxides can irreversibly react with ruthenium alkylidene catalysts and catalytic intermediates
. Dealing with O2
– Degas solution prior to the addition of catalyst
. Dealing with hydroperoxides
– Test for peroxides in substrate and solvent
– Store substrate and solvent over BHT
– Purification techniques vary by substrate
MATERIA 28 ETHYLENE IS NOT INNOCENT
. Ethylene can sequester catalyst and lead to decomposition
. Remove it during the reaction − Vacuum / nitrogen sparge / both − Use a more polar solvent . Vessel size and configuration matters!!! − Gas transfer effects − Volume to surface area ratio affects pressure & solubility
Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. MATERIA Soc. 2007, 129, 7961. 29 INTERNAL OLEFINS ENHANCE CATALYST LIFETIME
Entry Catalyst Substrate Conv. TON 1 C949 Acrylate 30% 6,000 2 C627 (HG-II) Acrylate 52% 13,800 3 C949 Crotonate 97% 31,100 4 C627 (HG-II) Crotonate 96% 35,450
Vignon et al ChemSusChem 2015, 8, 1143. MATERIA 30 INTERNAL OLEFINS IN TOTAL SYNTHESIS
Type I
C848
Type II
C627
MATERIA Wang, G.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 8088. 31 RESIDUAL RUTHENIUM REMOVAL
. Ru is Class 2B, same ICH limits as Pd (<10 ppm)
MATERIA ICH Harmonized Guideline, December 2014 32 RESIDUAL RUTHENIUM REMOVAL
Extraction • Imidazole - Brenner et al (Boehringer-Ingelheim, Germany) US7183374 (B2), 2007 . Mercaptonicotinic acid - Yee, N. K., et al J. Org. Chem. 2006, 71, 7133. . Cysteine - Wang, H. et al Tetrahedron 2009, 65, 6291. . THMP - Pederson et al Adv. Synth. Catal. 2002, 344, 728. . sCO2 - Gallou, F. et al Org. Process Res. Dev. 2006, 10, 937.
. Na2S2O5 - Wu, G. G et al WO2010028232, 2010. Adsorption
. H2, Pd/C - Wang et al Org. Process Res. Dev. 2008, 12, 226.
. H2, Pd/C - Kong, J. et al J. Org. Chem. 2012 , 77, 3820.
MATERIA Wheeler, P.; Phillips, J. H.; Pederson, R. L. Org. Proc. Res. Dev. 2016, 20, 1182. 33 FACILITATED BY MINIMAL CATALYST LOADING
Conditions: (i) Hoveyda-Grubbs II (0.2 mol%), 2,6-dichloroquinone (10 mol%), PhMe (13.5 vol), 100 °C (91%);
(ii) H2, Pd/C, PhMe/IPA, then crystallization from IPA/H2O (89%).
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. 34 Macrocyclizations on Scale BILN-2061 MACROCYCLIZATION
Early Development Conditions
C601 Hoveyda-Grubbs I
Context R = C601 Loading (mol %) Concentration Solvent Temp Yield
Initial Scale-Up PNB 5 0.01 M CH2Cl2 40 °C 87% Pilot Plant (>100kg) Brosyl 3 0.014 M PhMe 80 °C 87%
1. Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.-j.; Wei, W.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, J.; Tan, J.; Zhang, L.; Xu, J.; Smith-Kennan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M. Johnson, M. J. Org. Chem. 2006, 71, 7133. 2. Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, MATERIA 9, 513. 36 FURTHER OPTIMIZATION
Initiation Site Matters
Proposed Chelation
R = A:B H 96:4 Bn 85:15 Boc 0:100 Ac 0:100
Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, MATERIA V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303. 37 FURTHER OPTIMIZATION
Conformational Effects
Ring strain in product calculated to be ~2 kcal/mol lower when R= Boc versus H.
Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, MATERIA V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303. 38 FULLY OPTIMIZED CONDITIONS
Key Parameters . 2nd Generation Catalyst − Higher activity − Thermodynamic control of macrocycle vs oligomers . N-Boc protecting group − Favors cyclization by reducing ring strain − Prevents initiation at vinylcyclopropane (epimerization and chelation) . Diene solution degassed by refluxing prior to catalyst addition
Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. Org. MATERIA Process Res. Dev. 2009, 13, 250. 39 APPLIED TO SIMEPREVIR
Entry R = Time (h) Catalyst loading (mol %) SM (% by HPLC) Oligomer (% by HPLC) Product (% by HPLC)
1 H 20 3.5 59 28 11
2 COCF3 1 3.5 5 n.d. 69
3 COCF3 1 6.4 2 n.d. 94
4 COCF2Cl 1 6.4 n.d. n.d. 95
Horvath, A. et al (Janssen Pharmaceuticals, Inc., USA). Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC 435. PCT MATERIA Int. Appl. 2013061285, May 2, 2013. 40 VANIPREVIR OPTIMIZATION
Catalyst Loading Temp (°C) Additive Addition Method Conc (M) Yield of A (%) Yield of B (%) Oligomerization (%) 0.5 mol % 70 0 mol % Normal 0.09 62 8 5 0.5 mol % 70 10 mol% Normal 0.09 72 <1 5 0.2 mol % 70 10 mol% Normal 0.09 72 <1 5 0.2 mol% 100 10 mol% Normal 0.09 84 1.5 5
0.2 mol% 100 10 mol% With N2 Sparge 0.09 88 1.5 5
0.2 mol% 100 10 mol% With N2 Sparge 0.13 78 2 >15 0.2 mol% 100 10 mol% “Infinite Dilution” 0.13 91 2 5
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. 41 Capabilities, Services, and Support CATALYST MANUFACTURING AND AVAILABILITY
• Catalyst manufacturing facility in Pasadena, CA • Metric ton annual capacity • Kilogram quantities of popular catalysts typically in-stock • Secondary US manufacturer qualified
• Currently qualifying additional non-US toll manufacturers MATERIA 43 TECHNICAL SUPPORT
Print and Web Resources
MATERIA 44 CATALYST SCREENING
MATERIA 45 MATERIA’S INTERNAL RESOURCES
• >40 metathesis catalysts in-house • Specialized R&D team to help evaluate • Catalyst selection • Process optimization • Application development • Metric ton catalyst production capacity • Freedom to operate supported by broadest IP portfolio • Access to the latest catalyst innovations developed in Professor Grubbs’ labs • Easy procurement either through • Sigma-Aldrich for research quantities or • Directly from Materia for process scale-up and production requirements
MATERIA 46 Philip Wheeler, Ph. D. Business Development Manager (626) 584-8400 x298 [email protected] © 2016 Materia, Inc. www.materia-inc.com 60 N San Gabriel Blvd. www.allthingsmetathesis.com Pasadena, CA 91107