A Pharmaceutical Industry Perspective on Sustainable Metal Catalysis

Review Cite This: Organometallics XXXX, XXX, XXX−XXX

pubs.acs.org/Organometallics

A Pharmaceutical Industry Perspective on Sustainable Metal Catalysis John D. Hayler,† David K. Leahy,*,‡ and Eric M. Simmons§ †

API Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom Process Chemistry, Takeda Pharmaceuticals International, Cambridge, Massachusetts 02139, United States § Chemical & Synthetic Development, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States Downloaded via UNIV OF SUNDERLAND on October 4, 2018 at 15:07:00 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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ABSTRACT: As companies grow ever more mindful of the sustainability aspects of their products and supply chains, an increasing focus on the environmental impact of pharmaceutical manufacture spurs innovation from chemists who support this industry. Metal catalysis has the potential to greatly enhance the sustainability of pharmaceutical products, leading to shorter and more efficient synthetic routes and more direct access to single stereoisomeric products. This perspective article seeks to highlight a number of important considerations for the design of new and improved sustainable metal-catalyzed transformations in order to facilitate rapid adoption by the pharmaceutical industry.

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INTRODUCTION

DISCUSSION Step Economy. The desire to minimize the number of steps needed to prepare a target molecule comes second nature to organic chemists. For pharmaceutical process chemists, this translates into cost savings and lead time reductions, hence a highly desirable outcome that transition metal catalysis can enable. However, the necessity to preactivate substrates toward coupling can significantly erode these savings. For example, the Suzuki−Miyaura and other related C−C cross-coupling reactions typically require up to three activation steps to allow a single coupling to occur. The synthesis of ledipasvir, one of the two active ingredients in Gilead’s blockbuster HCV drug Harvoni, illustrates the step economy challenge for the Suzuki−Miyaura reaction (Scheme 1).8 Both aryl bromides are prepared (not shown) early in the synthetic sequence, but an efficient one-pot borylation/ Suzuki−Miyaura sequence is carried out, using the same catalyst for each of the two transformations thus mitigating some of these efficiency challenges. While C−H activation can offer a saving in step economy, it is often negated by the requirement of using a directing group.9 Such installation and subsequent removal of a transient directing group is rarely used in multikilo-scale synthesis; however, a more strategic use of a molecule’s inherent functionality as a directing group can offer a significant advantage. In Merck’s synthesis of anacetrapib, an oxazoline serves as both a directing group for a ruthenium-catalyzed

Transition metal catalysis has become foundational to modern pharmaceutical design and manufacture.1 From powerful crosscoupling methodologies that facilitate simple construction of C−C and C−X bonds, to asymmetric hydrogenations that almost trivialize the construction of various secondary stereocenters, transition metal catalysis has become widely utilized across the chemical community and particularly by the pharmaceutical industry. Interestingly, the Suzuki−Miyaura2 and Buchwald−Hartwig3 reactions are now among the top five reactions performed by medicinal chemists today, certainly influencing the design of modern pharmaceuticals.4 Undoubtedly, the modular and predictable nature of these transformations, along with the broad commercial availability of diverse coupling partners, make these reactions particularly appealing within the drug discovery space. For the process chemist, it is often extremely difficult to envision constructing the same molecules without employing these venerable reactions. Fortunately, the goals of green chemistry and process chemistry are very much parallel, and transition metal catalysis intersects with these goals directly. While the 12 principles of green chemistry,5 set forth by Paul Anastas and John Warner, highlight catalysis as number 9 on this list, it would be a fallacy to think that all catalysis is green, and this is especially true for transition metal catalysis. Life cycle considerations can dominate the supposed sustainability of a transition-metal-catalyzed process, once a more holistic view of metal mining, ligand synthesis, and substrate activation is taken into account. 6,7 This manuscript seeks to provide a pharmaceutical industry perspective on sustainable metal catalysis. © XXXX American Chemical Society

Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Received: August 7, 2018

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DOI: 10.1021/acs.organomet.8b00566 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 1

Scheme 2

Scheme 3

Scheme 4

palladium-catalyzed direct benzylation installs the second benzylic C−C bond, with exclusive regioselectivity. While in the case of carbon−heteroatom cross-couplings the activation of the nucleophile partners is rarely needed, other classical C−C coupling reactions, including the Heck and Sonogashira reactions, make use of the innate reactivity of the respective alkene and alkynes. More modern cross-electrophile couplings are effective in reducing the activation burden.12

direct arylation and a synthetic handle for further elaboration to the desired oxazolidinone (Scheme 2).10 Alternatively, cross-couplings exploiting a molecule’s innate reactivity also lead to highly step efficient processes. This concept is doubly illustrated in Eli Lilly’s synthesis of the JAK2 inhibitor, LY2784544, where a vanadium-catalyzed Miniscitype aminomethylation forms the target compound’s first benzylic C−C bond (Scheme 3).11 After decarboxylation, a B


Review


Scheme 6

Scheme 7

kilo-scale synthesis of the GlyT1 inhibitor PF-03463275 to overcome the lengthy workup and low yield associated with the traditional two-step reductive amination process (Scheme 6).18 Perhaps an unappreciated consideration outside of the process chemistry community is the position of a catalytic transformation within a synthetic route. Depending on the length of the synthesis, transition-metal-catalyzed reactions near the beginning of a synthetic route can often be cost prohibitive, given the much higher scale requirements of early steps. Therefore, any early catalytic processes have an even higher requirement to meet in terms of step efficiency and catalyst loadings. Conversely, transition-metal-catalyzed reactions located at the very end of a synthetic sequence present their own distinct challenges with regard to impurity control, both structurally related small molecule impurities as well as elemental impurities (vide infra), in meeting regulatory and quality requirements. As such, chemistries used at the end of a synthetic sequence should ideally provide very clean reaction profiles, and robust, efficient strategies for metal removal must be carefully considered. Interestingly, after amide formation, the Suzuki−Miyaura reaction and Buchwald−Hartwig reactions are among the top 3 final-step reactions in the discovery chemistry space;4 as noted earlier, these reactions lend themselves well to diversity-oriented approaches, especially given their reliability and readily available starting materials. Asymmetric Transformations. Many APIs are chiral molecules and asymmetric synthesis improves not only the material efficiency but also the step economy through the elimination of enantiomer separation stages or reliance upon transforming raw materials from the chiral pool. Asymmetric catalysis offers a wealth of opportunity in this space, but sustainability gains can be tempered by limitations associated with life-cycle considerations of the chiral ligand/metal

Pfizer, in collaboration with the Weix group, has successfully employed nickel catalysis with next-generation nitrogencontaining ligands in efficient reductive sp3−sp2 crosscouplings (Scheme 4), albeit at the cost of employing a stoichiometric zinc reductant.13 Nonetheless, catalyst-controlled direct, selective functionalization remains an ultimate goal of this type of cross-coupling, and while exciting developments have emerged from academia, much additional work is needed to bring these methodologies to the mainstream and render them practical for large-scale implementation.14 In particular, current limitations include factors such as robustness, predictability (to enable retrosynthetic analysis), generality, and a lack of mechanistic understanding. In an exciting contribution from Yu’s lab, in collaboration with researchers at Bristol-Myers Squibb, truly ligand-accelerated, nondirected C−H functionalization of arenes was described, as exemplified by selective olefination of the antileukemic and antitumor (+) camptothecin.15 Yu later found that orthogonal regioselectivity could be achieved for the same compound using a bifunctional template approach to remove site selectivity (Scheme 5).16 While these transformations represent the forefront of novel reactivity, they also illustrate some of the current challenges associated with C−H activation reactions, including the need for stoichiometric additives (in this case silver salts) and high catalyst (and template) loadings. Hydrogen-borrowing catalysis represents another class of cross-coupling methodology gaining recent prominence, where alcohols and amines can be directly combined to give the products of a formal reductive amination.17 These powerful reactions will often increase step economy and circumvent highly undesirable oxidation-state changes and the accompanying generation of stoichiometric byproducts. Pfizer made use of an iridium-catalyzed hydrogen-borrowing coupling in their C


Review


Scheme 9

Scheme 10

complexes themselves. Hence, the final enantioselectivity of a transformation is not the sole determinate of a reaction’s value, but rather the complexity added per “price paid” should be strongly considered. Asymmetric reduction has undoubtedly made the largest impact to the field of asymmetric catalysis. For example, in Knowles’ landmark synthesis of L-dopa, the desired (S)stereocenter is set with high enantioselectivity through a rhodium-catalyzed asymmetric hydrogenation of the Zenamide (Scheme 7).19 It is worth noting here that this Nobel Prize winning research came from an industrial lab at the Monsanto Company. While early asymmetric hydrogenations required substrates of fixed geometry, the application of asymmetric transformations in a dynamic kinetic resolution setting, pioneered by Noyori, another Nobel laureate, provides rich opportunities for simpler routes avoiding the need for stereospecific synthesis of the required substrate.20 This is exemplified by the Merck synthesis of a GRA antagonist, where the racemic ketone is converted to a single stereoisomer of the chiral alcohol product, via a ruthenium-catalyzed asymmetric hydrogenation/ kinetic resolution (Scheme 8).21 Central to Merck’s synthesis of sitagliptin was a rhodiumcatalyzed asymmetric hydrogenation of an unfunctionalized enamide (Scheme 9).22 Similar to the considerations for C−H activation chemistry (vide supra), installation and subsequent removal of an activating group inherently limits the overall efficiency of an asymmetric transformation, whereas harnessing

the innate functionality of molecule as a directing group, as in the sitagliptin hydrogenation, is significantly more advantageous. This approach was superseded by a biocatalytic transamination using an evolved enzyme in collaboration with Codexis, where despite the low catalyst loading of 0.15 mol % the cost savings of avoiding the metal catalyst/chiral ligand along with the fluctuating price of rhodium and the associated operational costs of high pressure hydrogenation (250 psi H2) at large scales were factors influencing this change.23 However, the key driver for the switch was that the ee from the asymmetric hydrogenation was low and required a crystallization step to upgrade prior to the API salt formation step, whereas the biocatalytic transformation gave near-perfect ee. This switch highlights the high bar required for asymmetric catalysis, especially given recent advances in enzyme engineering. Furthermore, classical resolutions, and especially various types of crystallization-induced dynamic resolutions,24 have proven effective in providing the same chiral centers obtained by metal catalysis, often at a lower cost and with a more environmentally benign footprint. The choice between biocatalysis and chemocatalysis is not always a straightforward one. To illustrate this point, Blaser et al. compared four routes for the synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate, an intermediate in the synthesis of a number of angiotensin converting enzyme (ACE) inhibitors (Scheme 10).25 Each route was developed by Ciba-Geigy and/or Solvias, in collaboration with Ciba Specialty Chemicals, and run on a D


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Organometallics

rhodium, and iridium, are in danger of becoming depleted within the next 50 years.32 The location of mineral reserves and competing industrial uses leads to considerations of the criticality of a metal33 and the risk34 to its continued supply; the platinum group metals (PGM), central to current catalysis feature high up in either analysis. Finally, the large-scale price flux seen in the commodities markets of precious metals, such as rhodium and iridium, presents a significant problem in commercial supply chain planning. In contrast, nonprecious first row or “base” metals such as iron,35 cobalt,36 nickel,37 and copper,38 have much greater Earth abundance and are thus both environmentally and economically advantageous compared to precious metals. For example, the cost of nickel is approximately $1/mol, 3 orders of magnitude less expensive compared to that of palladium, which currently costs around $3000/mol. Thus, processes catalyzed by first row metals have the potential to be significantly cheaper and more sustainable than an analogous process employing a precious metal catalyst. However, at present earth-abundant metals do not function as direct dropin replacements for many processes catalyzed by platinum group metals, and a dual approach of continued development of alternate catalyst systems, along with increased efficiency of precious metal recovery and recycling39 is required. An additional advantage of first row metals lies in their unique reactivity compared to second and third row metals. The increased nucleophilicity of nickel, as a result of its smaller size and decreased electronegativity as compared to palladium, makes it an effective catalyst for cross-couplings of C−O and C(sp3)−X bonds that are typically inert to palladium catalysts.37 Similarly, iron and cobalt catalysts have demonstrated promising reactivity for the hydrogenation of unactivated tri- and tetrasubstituted alkenes,40 which are notoriously challenging substrates for precious metal catalysts.41 However, compared to their second and third row counterparts, there has been much more limited ligand development for first row metals,42 resulting in a smaller array of ligands that are effective in catalytic transformations. First row metals also tend to undergo more facile ligand exchange and disproportionation, as well as to have multiple energetically accessible coordination geometries, oxidation states, and spin states, all of which complicate the development and mechanistic study of catalytic processes. In addition, many published transformations employ expensive and/or airsensitive catalyst precursors, such as Ni(cod)2,43 that are not only impractical for use on a large scale but also often negate the economic advantages offered by base metals. Even if an inexpensive metal precursor can be employed, the low cost of the metal will be offset if high loadings of an expensive ligand are required or if catalyst removal from the process stream is mass- and operation-intensive. Nonetheless, tremendous progress has been achieved in the past decade in addressing the factors that hinder the widespread application of first row metals in large-scale catalytic processes. The limited availability of ligands for nonprecious metals was targeted in the collaboration between the Weix lab and a group at Pfizer that was highlighted previously (see Scheme 4). This work demonstrated that mining pharmaceutical compound libraries which are typically rich in heterocycles containing N- and O-donor groups can be an effective means for identifying new ligand structural motifs for nickel-catalyzed C−C couplings.13 The practical limitations

multikilogram scale. Routes A and B made use of biocatalytic approaches, while routes C and D employed enantioselective hydrogenation using cinchona-modified platinum on alumina catalyst. Surprisingly, despite lower chemical yields in the reduction step (Rt. D 50%, cf. Rt. A 99%), the transition-metal-catalyzed routes had lower process mass intensity (PMI; Rt. D 40, cf. Rt. A 105 kg/kg) and higher space-time yields {Rt. C 24, cf. Rt. A 0.64−1.7 [(mol/(L day)]}.26 Route D provided the best economics, once the synthesis and cost of the starting materials are taken into consideration. The PMI and space-time yield advantages of metal-catalyzed vs biocatalytic routes is not uncommon, as the latter transformations are typically run at higher dilution in water, which can be a problem with lowsolubility compounds and can have PMI-intensive workups for removal of the enzymes. Nonetheless, continued enzyme evolution can provide opportunities for more practical applications of biocatalysis, and as the speed and availability of enzyme evolution continues to improve, the choice between bio- and chemocatalyzed approaches will increasingly depend on a holistic assessment of the route on a case-by-case basis. Enantioselective metal-catalyzed transformations, such as C−C bond formations, that give rise to structures not accessible via biocatalysis, chiral pool, or dynamic resolution will gain prominence and should continue to be the focus of much academic research. Metal Choice. The majority of metal-catalyzed transformations that are utilized in large-scale pharmaceutical synthesis involve second row and occasionally third row transition metals.27 In particular, palladium catalysts are most frequently utilized for C−C2 and C−N3 cross-couplings, while asymmetric hydrogenations are typically conducted with rhodium, ruthenium, and sometimes iridium catalysts.28 Though not as widely applied as cross-coupling or hydrogenation, ruthenium-catalyzed olefin metathesis has also been utilized on an industrial scale.29 The major advantages of precious metal catalysts are their broad substrate scope and well-studied mechanisms, which typically involve predictable oxidation states and discrete two-electron redox processes. Notably, a wide array of chiral phosphine ligands have been developed over the past several decades that promote the enantioselective reduction of a diverse array of unsaturated substrates with precious metal catalysts, and many of these systems are capable of operating with high turnover numbers that enable very low catalyst loadings to be utilized. However, there are also many disadvantages associated with the use of precious metal catalysts. From a sustainability perspective, the decreased earth-abundance of second and third row metals30 leads to a drastically higher environmental impact from their use compared to that of first row metals. It has been estimated that the global warming potential (GWP) for the production of 1 kg of palladium is 3880 kg equivalents of CO2 (e-CO2), while for rhodium this value is a staggering 35 100 kg e-CO2.31 For comparison, the production of 1 kg of nickel is calculated to have a GWP of 6.5 kg e-CO2, and iron has a GWP of just 1.5 kg e-CO2. Qualitatively similar trends can be observed for other environmental factors such as cumulative energy demand (CED), terrestrial acidification, and freshwater eutrophication, which collectively suggest that the net environmental impact from precious metal usage is approximately 3 orders of magnitude higher compared to that of first row metals. Additionally, the known reserves of many second and third row metals, including ruthenium, E


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Organometallics

sitagliptin.22 Similarly, in Bristol-Myers Squibb’s synthesis of CGRP antagonist BMS-846372, the lack of bulk quantities of BrettPhos within the time frame needed to satisfy campaign needs prompted the use of RuPhos in a palladium-catalyzed αarylation, despite the fact that the former ligand both gave higher yields and enabled lower catalyst loadings to be used (Scheme 13).48 In other cases, the lack of any effective alternative ligands may prevent development of the process altogether. It has recently been emphasized that common process metrics such as PMI ignore any contributions associated with the manufacture of reactants and reagents, which also includes catalysts and ligands.49 Some highly complex ligands are prepared through synthetic sequences of 10 or more steps, with associated PMIs of >1000.50 Depending on the amount of catalyst and ligand used and the placement of the catalytic step in the API synthetic sequence (vide supra), there may be a significant impact to cumulative PMI that is not immediately obvious unless these factors are explicitly taken into consideration.6,49 In practice, complex ligands tend to have higher associated costs, which suggests that ligand cost is strongly correlated to a rough estimate of the PMI (and associated environmental impact) resulting from its synthesis and corresponding use in a catalytic process. The lack of published life cycle information on ligand synthesis hinders a holistic assessment of alternative approaches. However, in a life cycle analysis comparison of a batch vs flow Buchwald−Hartwig amination of an intermediate in the synthesis of the AstraZeneca drug candidate AR-A2 (Scheme 14),51 Yaseneva et al. found that the production of (R)-BINAP palladium acetate (used in the batch process) and a palladium N-heterocyclic carbene system (used in the flow process), both contributed approximately 30% of the global warming potential of the process.6 While much effort has been invested in metal recovery, the ligand is often only a single-use component of a process. In all LCA of pharmaceutical manufacture, there is a good correlation between mass of materials used and other life cycle indicators (e.g., CED, GWP), with solvent making the largest contribution, as it did in the aforementioned study. Consequently, the shortest synthetic route from raw materials (greatest step economy) invariably has the lowest life cycle impact, which can be further reduced if materials are efficiently recovered, reused and recycled.

of air- and moisture-sensitive catalysts for iron- and cobaltcatalyzed hydrosilylation and hydroboration was overcome by in situ activation of air-stable [M]Cl2 precatalysts using NaOtBu, a strategy that was also applicable to manganese and nickel precatalysts.44 Very recently, Chirik and co-workers in collaboration with Merck developed a cobalt-catalyzed asymmetric hydrogenation of enamides with low catalyst loading using an inexpensive, air-stable CoCl2·6H2O precatalyst, which was applied to the asymmetric synthesis of levetiracetam on a 200 g scale (Scheme 11).45,46 Scheme 11

A pair of nickel-catalyzed borylation and Suzuki reactions were developed by Genentech for the synthesis of pictilisib (Scheme 12).47 Both reactions were conducted on a multikilogram-scale utilizing cheap and readily available Ni(NO3)2·6H2O (ca. $15/mol) as precatalyst, with the Suzuki coupling operating at an impressive 0.03 mol % catalyst loading. It is also worth noting that in both steps the residual nickel catalyst could be removed from the reaction mixture by simple aqueous washes and crystallization without the need for expensive metal scavengers often employed with palladium catalysts. Ligand Choice. In many cases, a ligand or catalyst may promote an efficient catalytic transformation, but a number of factors can hinder its use on bulk scale. This could be due to lack of commercial availability, poor scalability of its synthesis that makes it difficult to obtain large quantities within a reasonable time frame, or intellectual property restrictions that discourage use at scale. Even in cases where there is commercial availability at bulk scale without IP limitations, high cost can render use of a ligand or catalyst impractical. These factors will often result in the implementation of a less efficient process utilizing an inferior but more available ligand; for example, t-butyl-JOSIPHOS was selected over other ligands that gave superior ee during ligand screening to prepare Scheme 12

F


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Scheme 14

Scheme 15

Scheme 16

Processing Conditions. A common theme in the examples cited above is the use of homogeneous catalysis, where efficient recovery of the metal from the waste stream is desired, but it can often be thwarted when the metal is widely dispersed to the point where it is uneconomical to recover it. This problem runs counter to the desire for greater catalyst efficiency. Many metal-catalyzed processes in the manufacture of APIs have relatively poor catalyst efficiency, with high catalyst loadings and low turnover numbers when compared to the catalysts used in bulk chemicals manufacture. However, development of highly efficient catalysts can sufficiently reduce the cost of the catalyst to the point where recovery is not economic. In an example by Bristol-Myers Squibb, catalyst loadings as low as 0.02 mol % were realized for an enantio- and chemoselective hydrogenation of a diketone, making this

transformation more cost-effective then an enzymatic approach, despite the use of rhodium and a highly complex ligand (Scheme 15).52 Nonetheless, cost-effective methods to recover metals from dilute organic process streams would lead to further increases in sustainability for homogeneous precious-metal-catalyzed processes;53 for example, Berliner et al. compare methods for removal of iridium in their hydrogenborrowing publication.18 In addition, sequestering methodologies are often required to reduce the residual metal content in the product: vide infra. Catalyst immobilization offers considerable promise, and where it is used routinely, e.g. Pd/C hydrogenation, overall efficiency and catalyst recovery can both be very high. Translating homogeneous to heterogeneous catalysis presents a number of challenges, especially with respect to catalyst G


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stability and loss of reactivity.54 Amara et al. have reported an elegant demonstration of asymmetric catalyst immobilization in the rhodium-catalyzed asymmetric hydrogenation of an enamide intermediate in the synthesis of AstraZeneca's JAK-2 kinase inhibitor AZD1480.55 The original reaction was run using a homogeneous catalyst in batch mode and did not progress in favor of a transaminase route.56 The authors immobilized the catalyst onto an alumina/phosphotungstic acid support, running the heterogeneous hydrogenation in flow. The flow reaction proved superior in catalyst load, processing time and space-time yield [399 (g/L h) cf. 47] to prepare 1 kg of substrate. Also noteworthy is that the residual rhodium content in the product was reduced from 260 ppm in batch to 90% of its mass but is almost never present in the final product of a synthetic sequence. Greener borylation conditions were recently developed by Molander in collaboration with Merck using tetrahydroxydiboron [B2(OH)4 or BBA], which is approximately one-third of the MW of B2(pin)2 and thus has much higher atom economy.70 This reagent was utilized on a 65 kg scale by Takeda in the synthesis of TAK-117 (Scheme 17), with an impressive 0.05 mol % loading of the palladium catalyst.71 H


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Organometallics

(5) Anastas, P.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. (6) Yaseneva, P.; Hodgson, P.; Zakrzewski, J.; Falß, S.; Meadows, R. E.; Lapkin, A. A. Continuous Flow Buchwald−Hartwig Amination of a Pharmaceutical Intermediate. React. Chem. Eng. 2016, 1, 229−238. Only comparative LCA data is presented, and the percentage contribution of the metal to each catalyst system is not provided (7) In addition to these considerations, a complete “cradle-to-grave” life cycle analysis would comprehensively look at all economic externalities and energy burdens from mining, transport, refining, transforming, packaging/handling, waste, and/or recovery of the metal. (8) Scott, R. W.; Vitale, J. P.; Matthews, K. S.; Teresk, M. G.; Formella, M. G.; Evans, J. W. PCT Int. Appl. WO 2013184702 A1, 2013. (9) For reviews, see (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C−H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960−9009. (b) Wencel-Delord, J.; Glorius, F. C−H Bond Activation Enables the Rapid Construction and Late-Stage Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369−375. (10) Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.F.; O’Shea, P. D.; Davies, I. W. Preparative Scale Synthesis of the Biaryl Core of Anacetrapib via a Ruthenium-Catalyzed Direct Arylation Reaction: Unexpected Effect of Solvent Impurity on the Arylation Reaction. J. Org. Chem. 2011, 76, 1436−1439. (11) Campbell, A. N.; Cole, K. P.; Martinelli, J. R.; May, S. A.; Mitchell, D.; Pollock, P. M.; Sullivan, K. A. Development of an Alternate Synthesis for a Key JAK2 Inhibitor Intermediate via Sequential C−H Bond Functionalization. Org. Process Res. Dev. 2013, 17, 273−281. (12) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920−921. (b) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von Wangelin, A. Reductive Cross-Coupling Reactions between Two Electrophiles. Chem. - Eur. J. 2014, 20, 6828−6842. (13) Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. New Ligands for Nickel Catalysis from Diverse Pharmaceutical Heterocycle Libraries. Nat. Chem. 2016, 8, 1126−1130. (14) For a review, see Hartwig, J. F. Catalyst-Controlled SiteSelective Bond Activation. Acc. Chem. Res. 2017, 50, 549−555. (15) Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. LigandAccelerated non-Directed C−H Functionalization of Arenes. Nature 2017, 551, 489−493. (16) Zhang, Z.; Tanaka, K.; Yu, J.-Q. Remote Site-Selective C−H Activation Directed by a Catalytic Bifunctional Template. Nature 2017, 543, 538−542. (17) For reviews, see (a) Corma, A.; Navas, J.; Sabater, M. J. Advances in One-Pot Synthesis through Borrowing Hydrogen Catalysis. Chem. Rev. 2018, 118, 1410−1459. (b) Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. A Survey of the Borrowing Hydrogen Approach to the Synthesis of Some Pharmaceutically Relevant Intermediates. Org. Process Res. Dev. 2015, 19, 1400−1410. (18) Berliner, M. A.; Dubant, S. P. A.; Makowski, T.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y. Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor. Org. Process Res. Dev. 2011, 15, 1052−1062. (19) Knowles, W. S. Asymmetric hydrogenation. Acc. Chem. Res. 1983, 16, 106−112. (20) For a comprehensive review of transition-metal-catalyzed dynamic kinetic resolutions, see Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117, 4528−4561.

On the other hand, the palladium-catalyzed cyanation of aryl (pseudo)halides is often efficient from a PMI perspective but typically employs reagents such as KCN, NaCN, or Zn(CN)2, all of which have high acute toxicity and thus present a significant safety hazard to workers conducting these processes.72 In contrast, K4[Fe(CN)6]·3H2O is a nontoxic food additive that has been recently been shown to be a viable substitute for more toxic cyanide salts in the palladiumcatalyzed cyanation of aryl chlorides and bromides, which has the potential to significantly minimize the safety hazard for conducting these transformations on scale.73

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CONCLUSIONS The importance of transition metal catalysis to pharmaceutical design and manufacture over the last few decades cannot be overstated. Owing to its power to rapidly add complexity and efficiently construct biologically active molecules, adoption was rapid and remains firmly entrenched throughout all phases of drug discovery, development, and manufacture. However, the industry’s focus on sustainability, arguably, has lagged slightly, not gaining prominence until the early 2000s. By focusing on a holistic design of catalytic reactions that include more direct activation pathways, sustainable metals, less synthetically complex ligands, greener solvents, and highly active catalysts that can be easily separated and reused, this technology can a have a truly synergistic impact on sustainability in pharmaceutical manufacture.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected]. ORCID

John D. Hayler: 0000-0003-3685-3139 David K. Leahy: 0000-0003-4128-7792 Eric M. Simmons: 0000-0002-3854-1561 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Yi Hsiao and Dr. Jacob Janey (Bristol-Myers Squibb) for helpful discussions. REFERENCES

(1) (a) Dunn, P. J.; Hii, K. K.; Krische, M. J.; Williams, M. T. Sustainable Catalysis: Challenges and Practices for the Pharmaceutical and Fine Chemical Industries; John Wiley & Sons, Inc.: Hoboken, NJ, 2013. (b) Magano, J.; Dunetz, J. R. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177−2250. (2) For reviews, see (a) Suzuki, A. Recent Advances in the Cross-Coupling Reactions of Organoboron Derivatives with Organic Electrophiles. J. Organomet. Chem. 1999, 576, 147−168. (b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem., Int. Ed. 2012, 51, 5062−5085. (3) For reviews, see (a) Hartwig, J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides. Acc. Chem. Res. 2008, 41, 1534−1544. (b) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C−N CrossCoupling Reactions. Chem. Rev. 2016, 116, 12564−12649. (4) Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458. I


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Review

Organometallics

Using Tetrahydroxydiboron. Org. Process Res. Dev. 2017, 21, 65−74. (b) B2(OH)4 was also recently utilized by BMS in a telescope boylation/Suzuki process on 25 kg scale; see Smith, M. J.; Lawler, M. J.; Kopp, N.; McLeod, D. D.; Davulcu, A. H.; Lin, D.; Katipally, K.; Sfouggatakis, C. Development of a Concise Multikilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation−Suzuki Procedure. Org. Process Res. Dev. 2017, 21, 1859−1863. (72) (a) For a recent review, see Anbarasan, P.; Schareina, T.; Beller, M. Recent Developments and Perspectives in PalladiumCatalyzed Cyanation of Aryl Halides: Synthesis of Benzonitriles. Chem. Soc. Rev. 2011, 40, 5049−5067. (b) Reported toxicities (LD50, oral, rat): NaCN =4.7 mg/kg, KCN = 7.49 mg/kg, Zn(CN)2 = 54 mg/kg, K4[Fe(CN)6]·3H2O = 3613 mg/kg. (73) Senecal, T. D.; Shu, W.; Buchwald, S. L. A General, Practical Palladium-Catalyzed Cyanation of (Hetero)Aryl Chlorides and Bromides. Angew. Chem., Int. Ed. 2013, 52, 10035−10039 and reference therein .

Synthesis of an API Using Continuous Flow Solid-Supported Catalysis. Org. Process Res. Dev. 2016, 20, 1321−1327. (56) Frodsham, L.; Golden, M.; Hard, S.; Kenworthy, M. N.; Klauber, D. J.; Leslie, K.; Macleod, C.; Meadows, R. E.; Mulholland, K. R.; Reilly, J.; Squire, C.; Tomasi, S.; Watt, D.; Wells, A. S. Use of ω-Transaminase Enzyme Chemistry in the Synthesis of a JAK2 Kinase Inhibitor. Org. Process Res. Dev. 2013, 17, 1123−1130. (57) Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Using the Right Green Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable Processes. Org. Process Res. Dev. 2011, 15, 912−917. (58) Ashcroft, C. P.; Dunn, P. J.; Hayler, J. D.; Wells, A. S. Survey of Solvent Usage in Papers Published in Organic Process Research & Development 1997−2012. Org. Process Res. Dev. 2015, 19, 740−747. (59) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 Selection Guide of Classicaland Less Classical-Solvents. Green Chem. 2016, 18, 288−296. (60) Understanding REACH. https://echa.europa.eu/regulations/ reach/understanding-reach (accessed July 2018). (61) de-Bashan, L. E.; Bashan, Y. Recent Advances in Removing Phosphorus from Wastewater and its Future Use as Fertilizer (1997−2003). Water Res. 2004, 38, 4222−4246. (62) For reviews on methods for heavy metal removal, see (a) Fu, F.; Wang, Q. Removal of Heavy Metal Ions from Wastewaters: A review. J. Environ. Manage. 2011, 92, 407−418. (b) Carolin, C. F.; Kumar, P. S.; Saravanan, A.; Joshiba, G. J.; Naushad, M. Efficient Techniques for the Removal of Toxic Heavy Metals from Aquatic Environment: A review. J. Environ. Chem. Eng. 2017, 5, 2782−2799. (63) Henderson, R. K.; Hill, A. P.; Redman, A. M.; Sneddon, H. F. Development of GSK’s Acid and Base Selection Guides. Green Chem. 2015, 17, 945−949. (64) Consideration of solvents and reagents in the context of overall greenness requires a complex analysis that must be made from the perspective of overall process efficiency. For example, if a solvent is relatively hazardous but allows for more efficient catalysis or higher reaction concentration, then it may generate less overall waste compared to a more benign solvent choice, which could also potentially require more unit operations to remove it to prepare for isolation or the next step. (65) Quality Guidelines. http://www.ich.org/products/guidelines/ quality/article/quality-guidelines.html (accessed on June 2018). (66) It has been noted that the assessment of metal toxicity depends on a number of factors including oxidation state, solubility, and properties of their environment. For discussions, see (a) Egorova, K. S.; Ananikov, V. P. Which Metals are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts. Angew. Chem., Int. Ed. 2016, 55, 12150−12162. (b) Egorova, K. S.; Ananikov, V. P. Toxicity of Metal Compounds: Knowledge and Myths. Organometallics 2017, 36, 4071−4090. (67) For example, the 10 ppm permitted concentration for Pd is via the oral route, reducing to 1 ppm for parenteral and 0.1 ppm for inhaled administration. (68) For examples, see (a) Garrett, C. E.; Prasad, K. The Art of Meeting Palladium Specifications in Active Pharmaceutical Ingredients Produced by Pd-Catalyzed Reactions. Adv. Synth. Catal. 2004, 346, 889−900. (b) Gallagher, W. P.; Vo, A. Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media. Org. Process Res. Dev. 2015, 19, 1369−1373. (69) Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloarenes: A Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995, 60, 7508−7510. (70) Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. Scope of the Palladium-Catalyzed Aryl Borylation Utilizing Bis-Boronic Acid. J. Am. Chem. Soc. 2012, 134, 11667− 11673. (71) (a) Gurung, S. R.; Mitchell, C.; Huang, J.; Jonas, M.; Strawser, J. D.; Daia, E.; Hardy, A.; O’Brien, E.; Hicks, F.; Papageorgiou, C. D. Development and Scale-up of an Efficient Miyaura Borylation Process K


A Pharmaceutical Industry Perspective on Sustainable Metal Catalysis

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