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1 We will begin momentarily at 2pm ET Slides available now! Recordings will be available to ACS members after one week. Contact ACS Webinars at 1 Have Questions? Why am I muted? Don t worry. Everyone is muted except the presenter and host. Thank you and enjoy the show. Type them into questions box! Contact ACS Webinars at acswebinars@acs.org 2 1

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5 ACS Green Chemistry Institute Catalyzing and enabling the implementation of green chemistry and engineering throughout the global chemistry enterprise. Science Advancing research & development for global challenges Education Advocating progress in education & communication of green chemistry principles Industry Accelerating industrial adoption of green chemistry 9 The Call for Papers Opens January 4 th 2016!

6 Upcoming ACS Webinars Don t get caught in the cold register for our upcoming series! Upcoming ACS Webinars While you are enjoying your holidays, impress your guests with what you discover in ACS Webinars Archive!

7 Outsmarting the Shortage: The Emergence of Base Metal Catalysis in Pharma J. Chris McWilliams Director of Process Chemistry, Pfizer David Constable Director of the Green Chemistry Institute, ACS Slides available now! Recordings will be available to ACS members after one week Co-produced with the ACS Green Chemistry Institute 13 Supply of Critical Elements is not Sustainable 50% of all Zn is used to galvanize steel for corrosion resistance; 5-50 years of Zn are left at current rate of consumption Rh is one of the rarest elements in the Earth s crust accounting for parts per million; only 5-50 years of Rh are left. Global production of Sn = 140 tonnes; if current consumption continues, 5-50 years of Sn are left American Chemical Society ACS Green Chemistry Institute 14 7

8 What You Will Learn Metal-Catalyzed Cross-coupling, an important transformation in the Pharmaceutical Industry, still relies predominantly on Pd Base metals offer many advantages over Pd and other precious metals Base metals such as Ni, Cu, and Fe can be superior in performance to Pd, and should often be considered as the first approach rather than a replacement for Base metals offer new modes of reactivity and disconnections 15 Audience Survey Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT Have you run a cross-coupling reaction catalyzed by: Fe (iron) Ni (nickel) Cu (copper) All of the above None of the above 16 8

9 Pharmaceutical Research and Development Discovery and Early Development Compound Clinical Development Submission Launch and Marketing Pre-Clinical Study Phase I Phase II Phase III Filing Launch (Phase IV) Safety Safety Speed Broad Scope Reactions to assemble molecules Speed /Cost Quality Unique Connections Unique Chemical Space Robustness Environment Zhang, T. Y. Chem. Rev., 2006, 106, External Pharma Assessment Pd Cooper, Campbell, and Macdonald Angew. Chem. Int. Ed. 2010, 49, Roughly and Jordan J. Med. Chem. 2011, 54, Palladium Cross-Coupling = 17% of all transformations used to build NMEs Other Pd catalyzed transformations Hydrogenation/Hydrogenolysis, Bn/CBz deprotection 18 9

10 Metal Catalyzed Cross-Coupling R + R Metal Catalyst R R = Electrophile (Cl, Br, I, OTf, etc) = Nucleophile C=C ZnX B(OR) 2 MgX SnR 3 Heck Negishi Suzuki-Miyaura Kumada Stille Heck Negishi Suzuki C-N/C-O/C-S coupling 2010 Nobel Prize in Chemistry 19 Commercial Manufacturing of Drugs Pd (Suzuki) Xalkori (crizotinib) Lung Cancer Pd (Heck) Pd (Heck) Ibrance (palbociclib) Breast Cancer Rh (Hydrogenation) Pd (Hydrogenolysis) Pd (Hydrogenolysis) Xeljanz (tofacitinib) Rheumatoid Arthritis Pd (pi-allyl/enolate) Pd Hydrogenation Pd (Migita C-S coupling) Chantix (varenicline) Smoking Cessation Pd Hydrogenation Bosulif (bosutinib ) CML Pd (Heck) Inlyta (axitinib) Renal Cell Carcinoma Pfizer Confidential

11 Cross-Coupling on Scale Published reactions on >100 mmol scale Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, % 37% 22% 21 Audience Survey Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT Of those scaled reactions that have been published in the literature, what percentage are Pd catalyzed? About half About three-fourths All but 10% All but 5% 22 11

12 Cross-Coupling on Scale Published reactions on >100 mmol scale Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, Ni Kumada 37% 90% 23 Early Ni Cross-Coupling Reaction First of the cross-coupling reactions? Kumada et al J.Am.Chem.Soc. 1972, 94, 4374.the palladium-catalyzed reaction is much slower than the corresponding nickelcatalyzed reaction and does not appear to offer any advantage over the latter. Ei-Ichi Negishi et al J.C.S. Chem. Comm., 1976,

13 Audience Survey Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT Based upon current metal market costs alone, what would be the Pd catalyst loading that would be needed to be equal in cost for the same process that uses 1% Ni, Cu, or Fe? 0.1% 0.05% 0.01% <0.01% 25 Comparing Costs of Pd to Base Metals $700 $600 $500 $400 $300 $200 $100 $0 Cost $/Troy oz $643 $0.58 $0.22 $0.01 Pd Ni Cu Fe Metal Mol. Wt. $ / mol Pd ,207 Ni Cu Fe Pd catalyst loading equal in cost to 1% loading of Ni, Cu, or Fe = % 1 Troy oz = 31 g 26 13

14 Supply Metal Natural Abundance (ppm) Annual Production (tons) Supply Risk Index Leading Producers Pd Russia/S. Africa Ni 90 2,400, Russia Cu 68 18,700, China Fe 56,300 1,200,000, Chile 1 British Geological Society Risk Index WSJ, Toxicity and Environment Metal Oral Exposure Limits (ppm) Carbon Footprint (CO 2 e) Pd Ni Cu Fe oz Pd-Pt 1 ton of rock 28 14

15 16 years 12 years 1/26/2016 Base Metal Trivia Which metal has a lower energy transition state for oxidative addition, Pd or Ni? 29 The Nickel Suzuki-Miyaura Coupling Suzuki/Miyaura et al Tetrahedron Lett. 1979, 3437; Syn Comm. 1981, 11, 513 Percec et al J. Org. Chem. 1995, 60, 1060 Miyaura et al Tetrahedron Lett. 1996, 37, : Chatani, Garg, Shi 30 15

16 Ni Suzuki-Miyaura Coupling: A range of heterocycles and low catalyst loading Ge, S.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, Limitations in Scope Example: Suzuki-Miyaura Coupling Electrophile (dppf)ni(cin)cl 1 Ni(COD) 2 /PCy 3 2 Pd(OAc) 2 / XPhos 3 XPhos Palladacycle 3 < 1% 100% 100% 100% < 1% < 1% 100% 100% < 1% 3% 84% 100% < 1% < 1% 41% 61% Decomp < 1% < 1% Mostly Ph-Ph 1 Ge, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, Internal conditions 3 Zhou et al Eur. J. Org. Chem. 2012, Buchwald et al J. Am. Chem. Soc. 2013, 135, Pfizer Confidential

17 Challenges and Opportunities for Base Metals Complex Reaction Mechanisms Multiple Pathways proposed for Fe catalyzed Kumada Furstner et al J. Am. Chem. Soc. 2008, 130, 8773 Radical Chain Mechanism in Ni Reductive Coupling Biswas and Weix J. Am. Chem. Soc. 2013, 135, Base Metal Trivia Which metal is more likely to undergo beta-hydride elimination when bonded to an sp 3 carbon, Ni or Pd? 34 17

18 Examples of Base Metal Catalysis Asymmetric coupling with sp 3 centers Fu J. Am. Chem. Soc. 2015, 137, 9523 Beta-hydride elimination computational study (Ni vs. Pd) Morokuma J. Am. Chem. Soc. 1985, 107, 7109 Coupling with non-traditional electrophiles Chatani Org. Lett. 2014, 16, 5572 Alkyl Grignards with Functionalized ArX Furstner Org. Synth , 81, % Yield 15 g scale < 7 min 35 Nickel-catalyzed Suzuki cross-coupling in very early development NiCl 2 (PPh 3 ) 2 $1,300/mol PdCl 2 (dtbpf) $9,800/mol Catalyst (5 mol%) Temp ( C) Time (h) Conversion (%) (dppf)nicl (PPh 3 ) 2 NiCl (PPh 3 ) 2 NiCl (PPh 3 ) 2 NiCl PPh (dtbpf)pdcl

19 Initial supplies of a clinical candidate: Formation of a Boronic Acid 70 C Challenge Insufficient commercial supplies of Pd catalyst available 5% 54% Yield XPhos G-3 Catalyst 10% XPhos 37 Nickel catalysis works and is readily available 2% (Ph 3 P) 2 NiCl 2 Based on Molander precedent Molander et al J. Org. Chem. 2013, 78, % PPh 3 1:1 MeOH/ACN 20 C 90% Isolated Yield 1 st Generation 2 nd Generation 5% (XPhos)Pd G-3 2% Ni(PPh 3 ) 2 Cl 2 10% XPhos 4% PPh 3 70 C 20 C 54% Isolated Yield 90% Isolated Yield 90% Reduction in Cost Simple (and available) Catalysts System Milder Reaction Conditions 38 19

20 Pfizer Portfolio Application Initial FIH supplies route Difficult Pd purge 39 Nickel-Mediated Kumada Coupling 65% 40 20

21 Nickel-Mediated Kumada Coupling 65% Dimer (homocoupling) 41 Base Metal Trivia How might one reduce the amount of dimer formation? 42 21

22 Nickel-Mediated Kumada Coupling Slow addition reduces dimer formation Grignard Addition Yield (%) Fast 65 Slow (Syringe Pump) Iron Promoted Cross-Coupling 91% Isolated Yield Product 73 kg prepared to date T = 2 hours Starting Chloride Fe mediated coupling proceeds rapidly at room temperature 44 22

23 Base Metal Kumada Coupling 1 st Generation 2 nd Generation Comparison X = X = Br (MgBr) 5% Pd(PPh 3 ) 4 1% FeCl 3 77 C, DME 20 C, THF Mild Conditions Eliminates 1 bond-forming step and isolation of boronate ester Fe + No Ligand = No Cost catalyst and minimal environmental impact 56% Yield 91% Yield High yield, easy workup 10 ppm Pd limit 1300 ppm Fe limit No analytical method development or testing required 45 Published Scaled Ni Coupling An example from Genentech Tian et al Org. Process Res. Dev. 2013, 17, kg Simple PPh 3 as the ligand Cheap catalyst 19% improvement in yield over Pd alternative. Easy removal of the metal via aqueous ammonia wash Same coupling with (Ph 3 P) 2 Pd(Cl 2 ) requires a thio-silica treatment to remove Pd 46 23

24 Protocols to assess Ni catalysis Typical Procedures (pre-2015) n PR 3 + Ni(cod) 2 (cod) m Ni(PR 3 ) n + X cod m = 0,1, n = 2-4 X = 1,2 Unstable (thermal and air sensitive), cod is not an innocent bystander Reductant + (R 3 P) 2 NiCl 2 Ni(PR 3 ) Cl - Strong reductants and/or inefficient catalyst activation, ligand specific Very efficient reduction to (dppf)ni(0), but ligand specific Ge, S.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, Recently Developed Ni Precatalyst Received: March 09, 2015 Received: March 16, 2015 Two groups recognized the value of this precatalyst and submitted results within 1 week! 48 24

25 Recently Developed Ni Precatalyst Strem catalog # New Opportunities with Base Metals: Why Bother with the Nucleophile! Reductive coupling Weix et al J. Am. Chem. Soc. 2012, 134, 6146 Pfizer-Weix research collaboration ongoing soon to be published Reductive coupling with heterocyclic sp 3 halides Pfizer Medicinal Chemistry sponsored Molander, G.A.; Traister, K.M.; O Neill, B.T. et al J. Org. Chem. 2014, 79,

26 The Take-Away Messages Metal-Catalyzed Cross-coupling, an important transformation in the Pharmaceutical Industry, still relies predominantly on Pd Base metals offer many advantages over Pd and other precious metals Base metals such as Ni, Cu, and Fe can be superior in performance to Pd, and should often be considered as the first approach rather than a replacement for Base metals offer new modes of reactivity and disconnections 51 Acknowledgements Chemical Technology Javier Magano Sebastien Monfette Process Chemistry Alicia Guitierrez Shu Yu Bob Dugger Stéphane Caron Analytical R&D Andy Palm Steve Chesnut Pfizer Technology and Innovation Group Pharma Non-Precious Metal Catalysis Alliance Members Juan Colberg 52 26

27 Outsmarting the Shortage: The Emergence of Base Metal Catalysis in Pharma J. Chris McWilliams Director of Process Chemistry, Pfizer David Constable Director of the Green Chemistry Institute, ACS Slides available now! Recordings will be available to ACS members after one week Co-produced with the ACS Green Chemistry Institute 53 Upcoming ACS Webinars Don t get caught in the cold register for our upcoming series!

28 Outsmarting the Shortage: The Emergence of Base Metal Catalysis in Pharma J. Chris McWilliams Director of Process Chemistry, Pfizer David Constable Director of the Green Chemistry Institute, ACS Slides available now! Recordings will be available to ACS members after one week Co-produced with the ACS Green Chemistry Institute 55 The Call for Papers Opens January 4 th 2016!

29 How has ACS Webinars benefited you? This ACS Webinar was very supportive of my goals! I am promoting Greener is Safer and Safer is Greener in Washington State. The education given here to teachers needs vast improvements. Data from people like Sigma-Aldrich are the bullets for my program promotions. Thank you for the work you do! Michael Holst, NASA Endeavor STEM & Science PD Trainer Be a featured fan on an upcoming webinar! Write to acswebinars@acs.org 57 youtube.com/acswebinars Search for acswebinars and connect! 58 29

30 Benefits of ACS Membership Chemical & Engineering News (C&EN) The preeminent weekly news source. NEW! Free Access to ACS Presentations on Demand ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events. NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more ACS Webinars does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society. Contact ACS Webinars at 60 30

31 Upcoming ACS Webinars While you are enjoying your holidays, impress your guests with what you discover in ACS Webinars Archive!