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1/26/2016
“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
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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 0.0002 parts per million; only 5-50 years of Rh are left. American Chemical Society
Global production of Sn = 140 tonnes; if current consumption continues, 5-50 years of Sn are left
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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
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Pharmaceutical Research and Development Discovery and Early Development
Pre-Clinical Study
Compound Clinical Development
Phase I
Phase II
Submission
Phase III
Launch (Phase IV)
Filing
Safety
Safety
Broad Scope
Speed
Unique Connections
Launch and Marketing
Reactions to assemble molecules
Unique Chemical Space
Speed /Cost
Robustness
Quality
Environment
Zhang, T. Y. Chem. Rev., 2006, 106, 2583.
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External Pharma Assessment
Pd
Palladium Cross-Coupling = 17% of all transformations used to build NMEs Cooper, Campbell, and Macdonald Angew. Chem. Int. Ed. 2010, 49, 8082 – 8091 Roughly and Jordan J. Med. Chem. 2011, 54, 3451–3479
Other Pd catalyzed transformations Hydrogenation/Hydrogenolysis, Bn/CBz deprotection 18
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Metal Catalyzed Cross-Coupling Metal Catalyst R’
+
R’
R
Negishi
Suzuki
R
= Electrophile (Cl, Br, I, OTf, etc) = Nucleophile
C=C
Heck
ZnX
Negishi
B(OR)2
Suzuki-Miyaura
MgX
Kumada
SnR3
Stille
Heck
2010 Nobel Prize in Chemistry
C-N/C-O/C-S coupling
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Commercial Manufacturing of Drugs Pd (Heck)
Pd (Suzuki)
Pd (Hydrogenolysis)
Rh (Hydrogenation)
Pd (Heck)
Ibrance (palbociclib) Breast Cancer
Xalkori (crizotinib) Lung Cancer
Pd (Hydrogenolysis) Xeljanz (tofacitinib) Rheumatoid Arthritis
Pd Hydrogenation
Pd (pi-allyl/enolate)
Pd Hydrogenation Chantix (varenicline) Smoking Cessation
Bosulif (bosutinib ) CML
Pd (Migita C-S coupling)
Pd (Heck) Inlyta (axitinib) Renal Cell Carcinoma Pfizer Confidential │ 20
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Cross-Coupling on Scale Published reactions on >100 mmol scale Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
8% 37%
22%
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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%
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Cross-Coupling on Scale Published reactions on >100 mmol scale Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
Ni Kumada
37%
90%
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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, 596
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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%
•
