Ring-Closing Metathesis in Pharmaceutical Development

Review pubs.acs.org/OPRD

Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Ring-Closing Metathesis in Pharmaceutical Development: Fundamentals, Applications, and Future Directions Miao Yu,* Sha Lou,* and Francisco Gonzalez-Bobes*

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Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903-0191, United States ABSTRACT: Ring-closing metathesis (RCM) has become indispensable in organic synthesis for both academic investigations and industrial applications. This review provides an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. Key elements of reaction design and lessons learned from these applications are discussed to help those considering implementing RCM reactions on scale, particularly in manufacturing active pharmaceutical ingredients (APIs). Advances in the development of more effective catalysts and new methodologies, such as enantioselective RCM and stereoselective macrocyclic RCM, are also briefly discussed. KEYWORDS: ring-closing metathesis, industrial application, process development, reaction scale-up, pharmaceutical manufacturing

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CONTENTS

1. Introduction 2. Commonly-Used Olefin Metathesis Catalysts 2.1. Ruthenium-Based Olefin Metathesis Catalysts 2.2. Molybdenum-Based Olefin Metathesis Catalysts 3. Practical Considerations in Application of RingClosing Metathesis Reactions in Pharmaceutical Development 3.1. Defining the Cyclization Strategy 3.2. Desired RCM versus Other Reaction Pathways 3.3. Impact of Substrate Conformation 3.4. Selecting the Right Catalyst 3.5. Reaction Parameters: Concentration and Temperature 3.6. Ethylene Removal To Prevent Catalyst Decomposition and Reduce Undesired Reaction Pathways 3.7. Input Quality Control 3.8. Solvent Effects 3.9. Deactivation and Removal of Ru-Related Byproducts 4. Recent Advances in Ring-Closing Metathesis Reactions 4.1. Other Ruthenium-Based Catalysts with Enhanced Reactivity 4.2. Enantioselective Ring-Closing Metathesis 4.3. Stereoselective Formation of Alkenes in Macrocyclic Rings 5. Conclusion Author Information Corresponding Authors ORCID Notes Acknowledgments References © XXXX American Chemical Society

1. INTRODUCTION Olefin metathesis reactions have broadly impacted organic synthesis over the past few decades. In particular, alkene ringclosing metathesis (RCM) reactions are widely used in synthesis.1,2 Carbocyclic and heterocyclic compounds of many ring sizes are accessible by this powerful reaction. While five- and six-membered rings can be prepared conveniently, the synthesis of medium and macrocyclic alkene rings by RCM can be more challenging in terms of selectivity for the desired cyclization versus oligomers or undesired alkene isomers. Though RCM has been widely used in academic laboratories and drug discovery for the syntheses of numerous biologically active and structurally complex molecules, examples of its application in the pharmaceutical industry on production scales are still rare. Summarized in Figure 1 are representative applications of RCM reactions for production of active pharmaceutical ingredients (APIs) that have been commercialized or advanced in clinical studies. Among these examples, RCM reactions were mainly used to address the challenge of preparing macrocyclic peptides, common structural motifs in HCV NS3/4A serine protease inhibitors. Pioneering work to scale up an RCM reaction was reported by BoehringerIngelheim in 2005 for preparation of the 15-membered macrocyclic alkene in ciluprevir (BILN-2061).3 Additional examples of the construction of other complex macrocyclic rings have been reported by teams at Janssen,4 AbbVie,5 Merck,6 and Roche.7 In other cases, functionalities, such as the azapane in relacatib8 and the spirocyclic amine in rolapitant,9 were accessed efficiently with RCM followed by hydrogenation of the alkene products. Considering the increasing interest in the therapeutic potential of macrocyclic compounds as pharmaceutical candidates,10 the application of RCM reactions in process chemistry settings may increase in the future. Herein we aim to

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Received: April 5, 2018 Published: June 22, 2018 A

DOI: 10.1021/acs.oprd.8b00093 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Review

Figure 1. Representative examples of APIs prepared by RCM reactions.

Figure 2. Commonly used olefin metathesis catalysts.

provide an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. The goal is not just to provide a review of applications in pharmaceutical development but also to highlight key elements of reaction design and lessons learned from these scale-up studies that may help those considering applying RCM reactions on scale. The review includes a brief introduction of fundamental aspects of RCM reactions that may influence the development of an RCM reaction and practical aspects of reaction development, mostly from examples of RCM applications in manufacturing of APIs. Recent literature examples of new catalysts and methodologies in the field, such as enantioselective RCM and stereoselective macrocyclic RCM, are also briefly discussed. A comprehensive review of the RCM field is outside the scope of this

contribution. Many specialized monographs and reviews exist for those interested.11,12

2. COMMONLY-USED OLEFIN METATHESIS CATALYSTS Catalyst development has been an area of major focus in the field of olefin metathesis. Through a fundamental understanding of reaction mechanism and the use of organometallic design principles, a series of remarkable catalysts have been developed and enable reactions that were either not feasible before or delivered unprecedented efficiency and selectivity. In this section, ruthenium- and molybdenum-based olefin metathesis catalysts commonly used in metathesis reactions (Figure 2) are briefly discussed, including highlights of their discovery B



Review

Scheme 1. Mechanistic Investigations of Olefin Metathesis Reactions with Ru-2

Scheme 2. Mechanism of Olefin Metathesis Reactions with Ru-3

Ru-1.18 Remarkably, Ru-2 is capable of catalyzing metathesis reactions involving substituted olefins and electron-poor olefins, where Ru-1 is ineffective.15,18,19 Though the improved activity of Ru-2 was initially attributed to the enhanced phosphine dissociation rate, kinetic data indicated a lower rate of phosphine dissociation than that of Ru-1.20 Catalysts containing an NHC ligand, however, demonstrated a higher preference for coordination of the olefin substrate instead of recoordination of phosphine, which is likely due to the increased donor effect of the NHC that stabilizes metal-toolefin back-bonding to a much greater extent for π-acidic olefinic substrates than σ-donating phosphine ligands. As shown in Scheme 1, the active 14-electron phosphine-freecomplex I21 is generated via a dissociative mechanism, and the forward reaction (coordination of the olefin) is significantly faster than rebinding of phosphine (k2 > k−1). Catalyst stability in solution is a major factor that limits turnover numbers (TONs), particularly in reactions involving more challenging substrates, in many cases resulting in the need for high catalyst loadings and/or continuous addition of fresh catalyst to the reaction mixture. This can be a major issue for applications on large scales. The first-generation catalysts, such as Ru-1, decompose through either unimolecular or bimolecular pathways and undergo rapid decomposition in solution when exposed to oxygen, in spite of their excellent stability in the solid state.22 The second-generation catalysts, such as Ru-2, display better thermal stability than the firstgeneration catalyst Ru-1 both in the solid state and in solution.18−20,22 The enhanced thermal stability of the secondgeneration catalysts is attributed to the reduced rates of phosphine dissociation.19 In addition, NHC ligands offer steric and electronic stabilization of the coordinately unsaturated 14electron intermediate (e.g., I), which improves the catalyst longevity.23 Further improvement of catalyst stability was achieved by the Hoveyda group in 1999.24 Treatment of 2-isopropoxystyrene with Ru-1 generated a new complex, Ru-3, which exhibits exceptionally high stability toward air and moisture and allows catalyst recycling because of its stability toward silica gel

and mechanisms of action and comparisons of their reactivities and stabilities. 2.1. Ruthenium-Based Olefin Metathesis Catalysts. The first well-defined and metathesis-active ruthenium-based catalyst13 was discovered in 1992 by the Grubbs group, who reacted 3,3-diphenylcyclopropene with RuCl2(PPh3)4; however, the complex showed low reactivity and was effective only in the ring-opening metathesis polymerization (ROMP) of norbornene.13a Substitution of PPh3 with PCy3 increased the metathesis activity of the complex and led to the discovery of Ru-0, which was effective in catalytic RCM.13b,c The composition of two anionic and two neutral ligands of Ru-0 still represents the structural design of most current Ru-based olefin metathesis catalysts; however, the lengthy synthesis of the cyclopropane and the low initiation rate of the resultant diphenylvinyl carbene have limited the synthetic utility of the complex. To address these issues, in 1996 the Grubbs group prepared benzylidene complex Ru-1, which is widely referred as the “first-generation Grubbs catalyst”.13d Extensive mechanistic investigations have revealed that the first-generation catalysts engage in catalysis via a dissociative pathway through a 14-electron complex. Phosphine dissociation is the ratedetermining step, as the 14-electron complex is prone to recoordinate with free phosphine even in the presence of an excess amount of electron-rich olefins.14 While Ru-1 has demonstrated good reactivity in many olefin metathesis reactions, there are still several cases in which it is ineffective, such as reactions involving electron-poor or substituted olefins.15 The use of N-heterocyclic carbene (NHC) ligands16 led to major advances in the field of Ru-catalyzed metathesis reactions. Replacing one phosphine ligand with an NHC ligand was hypothesized to favor the dissociation of the trans phosphine from ruthenium because of the stronger σ-donor ability of NHCs relative to phosphine ligands,17 generating the active 14-electron catalyst. The new complex, Ru-2, commonly called the “second-generation Grubbs” catalyst, demonstrated enhanced catalytic activity in the RCM of diethyl diallylmalonate at a rate 100−1000 times greater than that observed with C



Review

Scheme 3. Three Possible Options for the Macrocyclic RCM Route to Vaniprevir (4)

and cylindrocyclophanes34 as well as the medium rings in FR90048235 and balanol.36 In comparison with the aforementioned ruthenium-based catalysts, Mo-1 is more sensitive to air and moisture. Thus, these complexes have seldom been considered for achieving RCM processes for large-scale plant operations, in which catalyst stability and ease of handling become key factors.

column chromatography. Studies in a model reaction indicated that Ru-3 initiates RCM 30 times slower but propagates 4 times faster in the catalytic cycle than Ru-1. The improved propagation rate supports the intermediacy of an olefin complex and is consistent with the known rate-retarding effects of phosphine recoordination.14a The relatively low initiation rate associated with Ru-3 can be explained by the less facile dissociation of the chelating styrenyl ether ligand, whereas Ru-1 initiates by the more facile dissociation of PCy3 to form the 14-electron complex (Scheme 2). Combining the improved stability due to the chelated styrenyl ether ligand of Ru-3 and the enhanced catalytic reactivity due to the NHC ligand of Ru-2, the Hoveyda group reported catalyst Ru-4 in 2000.25 The so-called “Hoveyda” or “Hoveyda−Grubbs” catalyst not only demonstrates excellent reactivity but also is extremely robust toward air and moisture. Additionally, Ru-4 was shown to be recyclable, an important economical consideration for most commercial processes. In comparison with the aforementioned catalysts, Ru-4 displays broad substrate scope and reactivity,26 including electron-poor olefin substrates such as acrylonitriles,27 fluorinated alkenes,28 sulfones,29 and vinyl chlorides.30 2.2. Molybdenum-Based Olefin Metathesis Catalysts. In addition to the ruthenium-based catalysts, high-oxidationstate molybdenum- and tungsten-based alkylidenes are also efficient catalysts, which may provide complementary modes of reactivity as well as functional group tolerance. Among the catalysts developed since the discovery of a tantalum-based alkylidene complex in the 1970s,31 the four-coordinate 14electron alkylidene complex Mo-1 (Figure 2), known as “Schrock’s catalyst”, was identified to afford high reactivity and functional group tolerance in olefin metathesis reactions.32 Mo-1 has been applied in many RCM reactions for the synthesis of biologically relevant molecules, where the same transformations were significantly less efficient with Ru catalysts. Such an advantage has been demonstrated in the formation of macrocyclic rings in fluvirucin B1 (Sch 38516)33

3. PRACTICAL CONSIDERATIONS IN APPLICATION OF RING-CLOSING METATHESIS REACTIONS IN PHARMACEUTICAL DEVELOPMENT 3.1. Defining the Cyclization Strategy. Cost considerations of a commercial API manufacturing process often drive the improvement of the process efficiency under constrained timelines for pharmaceutical development. Though process efficiency is dictated by many parameters, it is often significantly affected by the selected route, and the process cannot be extensively optimized until the synthetic route is defined.37 Consequently, as the cyclic molecule progresses through pharmaceutical development to the stage of on-scale production, the first goal of process development is the identification of the most efficient cyclization strategy if required. Vaniprevir (4) is a macrocyclic HCV NS3 protease inhibitor developed by Merck. An RCM-based approach to the 20membered macrocyclic intermediate was identified as a scalable route, as all of the key components could be assembled together in a convergent manner with minimal linear steps.6 As shown in Scheme 3, three possible RCM options were evaluated for macrocyclization with precursors that contain styryl−homoallyl, allyl−allyl, and homoallyl−vinyl dienes. According to a prior attempt by the same group, employing styryl−homoallyl diene 10 in RCM required a high catalyst loading (>10 mol %) to obtain a satisfactory yield, which could not be further improved by screening of catalysts and reaction conditions.38 The RCM with allyl−allyl diene precursor 13 toward intermediate 12 was further investigated, D



Review

Scheme 4. Alternative Macrocyclization Strategies for Vaniprevir (4)

Scheme 5. Synthetic Strategies for Rolapitant (9)

the low reactivity and side reactions. The Sonogashira reaction of 23 also afforded the macrocyclic product 20 in only 34% yield because of the generation of a substantial amount of dimer even under high-dilution conditions (5 mg/mL or 0.008 mM). In contrast, subjecting 25 to HATU- or EDC/HOPOmediated macrolactamization conditions led to the formation of 24 in up to 75% yield, which served as another robust and cost-effective approach to vaniprevir instead of using the RCM reaction to build the macrocycle. Eventually, the macrolactamization approach was selected as the commercial manufacturing route to vaniprevir,41 mainly because of its ease of operation on-scale, as the RCM reaction requires slow addition of both the substrate and the catalyst solutions simultaneously to refluxing toluene.6 Another example of defining a cyclization strategy was illustrated in the synthesis of rolapitant (9), a selective NK1 receptor antagonist that has been approved for the treatment of chemotherapy-induced nausea and vomiting.9 The core structure is a diazaspirocyclic ring that contains two quaternary stereogenic centers (Scheme 5). The initial approach to build the spirocycle involved nitro reduction followed by lactamiza-

as 13 is more straightforward to access than the homoallyl− vinyl substrate 15. Retrosynthetically, diene ester 13 could be derived from sequential couplings of allyl isoindoline HCl salt 16, prolinol ester 17, and ene acid 18. By this strategy, the synthesis of vaniprevir can be achieved with a longest linear sequence of only nine steps. In the synthesis of vaniprevir, besides the RCM route, alternative strategies to construct the 20-membered macrocycle were also investigated, including palladium-catalyzed cross-coupling reactions and macrolactamization (Scheme 4).38 As a large number of Pd-catalyzed cross-coupling reactions and the corresponding catalysts were available to explore the approach, several substrates were generated to evaluate Heck, Suzuki,39 and Sonogashira40 reactions toward macrocyclic intermediates 19 or 20. For the Heck reaction of 21, the optimal conditions led only to formation of the product in 47% yield, which was achieved under high-dilution conditions (8 mg/mL or 0.013 mM), and competing oligomerization, debromination, and 19-membered ring formation were encountered. Suzuki cyclization of 9-BBN adduct 22 provided only a trace amount of product because of E



Review

Scheme 6. Possible Reaction Pathways in RCM Reactions

cantly depending on the thermodynamic preference, the competence of the catalyst, and the rate of competing catalyst decomposition pathways under the experimental conditions (i.e., temperature, concentration, etc.). 3.3. Impact of Substrate Conformation. Since RCM reactions can be reversible depending on the experimental conditions and catalyst choice, thermodynamic factors are particularly relevant for selective formation of the desired product. Among all factors, ring strain in the product is one of the major contributors that determines the ease of RCM. It increases significantly in medium rings because of the staggering and transannular interaction between atoms forced into proximity from opposite sides of the ring.45 Though ring strain diminishes in macrocyclic rings, it still remains higher than in five- or six-membered rings. Studies from the Grubbs and Bach laboratories revealed that ring size has a significant influence on the selectivity of RCM reactions versus formation of acyclic dimers simply by altering the number of methylenes on the diene chain.46 Structural restriction of rotation is another factor for effective RCM, which may reduce the entropic penalty incurred upon ring closure. RCM tends to work better in the presence of conformational constraints that favor ring formation, such as appropriate substitutions on the diene chain (Thorpe−Ingold effect47). These conformational constraints may include the presence of another ring, a gemdimethyl group, or functionalities introducing rigid frameworks on the substrate chain.48 Therefore, diethyl diallylmalonates are broadly studied RCM substrates used to evaluate the reactivities of different metathesis catalysts. Other examples of designing suitable RCM substrates to bring the two reacting olefinic sites in closer proximity for cyclization include the installation of a removable pentafluorobenzyl group that is proposed to favor intramolecular π-stacking interactions49 as well as the removal of a structurally rigid functionality to alleviate unfavorable conformational bias.50 Other than modification of the substrate structure to facilitate ring closure, addition of a Lewis acid to RCM reactions of ester-containing substrates can restrain the conformational mobility to increase the probability of the intramolecular reaction. RCM reactions of such substrates to form medium or macrocyclic rings is typically challenging since the Z conformation of esters is preferred because of hyperconjugation and the dipole effect. In order to achieve proximity for intramolecular cyclization, isomerization of the Z conformer to the E conformer is required; therefore, such substrates likely oligomerize under metathesis conditions. Ti(OiPr)451 and the more sterically

tion of piperidine intermediate 26 to prepare the pyrrolidinone ring.42 Compound 26 was synthesized from 27 by alkylation with a Michael acceptor; 27 was prepared by nitration/ reduction of 28, which can be obtained in five steps from NCbz-L-Phg-OH. An efficient synthesis of 9 was completed in 10 total steps; however, installation of the second quaternary center of 27 resulted in poor control of the stereochemistry, which required separation of diastereomers by crystallization. Therefore, alternative strategies to build the spirocycle with high diastereoselectivity were evaluated, and RCM was deemed to be effective for this purpose.9 Chiral intermediates 30 and 31 were accessed from commercially available materials in six and five steps, respectively, and thus, the stereoselectivities of two quaternary centers were controlled independently. Coupling of the two fragments by reductive amination generated diene 29, which was subjected to RCM conditions followed by hydrogenation to deliver 9 in two steps. Though a total of 14 steps were required, the new strategy was considered advantageous because of the improved stereocontrol and the more convergent synthesis (nine steps for the longest linear sequence). 3.2. Desired RCM versus Other Reaction Pathways. As in any other cyclization method, the synthetic efficiency of an RCM reaction is limited by the competition between the desired intramolecular RCM and intermolecular dimerization or oligomerization reactions. As depicted in Scheme 6, once the catalyst initiates the metathesis process on the diene substrate, it not only can undergo ring closure to give the desired RCM product but also can react with another molecule of substrate through cross-metathesis (CM) to generate a dimer. The dimeric compound, which contains two terminal olefins, can then either undergo RCM to form the cyclic dimer or further react with other diene molecules to form an oligomer. Because of the nature of olefin metathesis, all of these steps can be reversible depending on the substrate structures, the reaction conditions, and the catalyst being employed.43 Accordingly, synthesis of five- or six-membered rings by RCM is typically straightforward, with superior selectivity versus undesired reaction pathways. In RCM reactions producing medium or macrocyclic rings, it is relatively difficult to predict which reaction conditions will deliver the optimal result. Therefore, efficient formation of the desired ring closure cannot always be guaranteed. It should be noted that the desired RCM product sometimes can be generated from undesired acyclic dimers, which requires the catalyst to react with the internal olefinic site.44 The RCM product, dimer, and oligomer distributions can vary signifiF



Review

Table 1. Conformations of RCM Precursors and Ring Sizes of RCM Products Influence RCM Performance

entry

substrate/product

substrate structure

proline cis:trans

conv./yield

Z:E selectivity

1 2 3

32a/33a 32b/33b 32c/33c

R1 = H; n = 2; R2 = R3 = H R1 = NHBOC; n = 2; R2 = OMe; R3 = Ph R1 = NHBOC; n = 1; R2 = OMe; R3 = Ph

1:1 1:9 1:9

90% yield of cyclized product 41. The mass balance was attributed to the formation of oligomers and dimers; cyclic dimers were also clearly observed by LC−MS. For the cyclization of diene 40, second-generation Ru catalysts were kinetically more reactive than first-generation ones but still generated considerable amounts of dimers. Separating these dimers from the desired RCM product was challenging and required a number of crystallizations of the RCM product or downstream intermediates. It is also worth noting that because the active catalyst is capable of ring-opening the RCM product, if the catalyst is not completely deactivated, evaporation of solvent can potentially result in extensive decomposition during solvent distillation unit operations. Thus, the Ru catalysts are preferably deactivated before concentration of the RCM reaction streams (see the discussion of catalyst deactivation in section 3.9). Another approach to accommodate the required high dilution is to add the substrate slowly to limit intermolecular reaction pathways, as demonstrated in the preparation of simeprevir, the first commercialized drug prepared using an RCM reaction on-scale (Scheme 8).4 Ruthenium−indenylidene complex Ru-7,66 which is straightforward to prepare and quite resistant to deactivation at high temperature, was identified as the optimal catalyst. The transformation initially suffered from oligomerization even under high dilution (0.01 M). Interestingly, protecting one of the amides with a BOC group enabled a 5-fold increase in concentration (0.05 M). To further minimize the intermolecular reaction of 42, the diene

was slowly added to refluxing toluene. Moreover, to minimize catalyst deactivation at 110 °C, Ru-7 was added slowly to the reaction mixture, which allowed a reduction in the catalyst loading from 2.5 to 0.3 mol %. Temperature can be another key aspect affecting the product distribution. Higher temperatures in some cases allow for conversion of kinetic products to the thermodynamically favored products but may adversely affect the catalyst lifetime. From an entropic viewpoint, if the re-equilibration takes place, it will favor the formation of the cyclic RCM product over acyclic and cyclic dimers or oligomers at elevated temperature. The RCM process produces two olefins (the RCM product and ethylene) from one molecule of the substrate; the acyclic dimerization produces one linear dimer and ethylene from two molecules of the substrate; the cyclic dimerization process produces one cyclic dimer and two molecules of ethylene from two molecules of the substrate. Thus, higher temperature in general reduces ΔG by reinforcing the entropic bias to favor the RCM process, which introduces a higher degree of disorder over dimerization under thermodynamic conditions. This strategy has been employed in many cases, including the onscale examples discussed above, particularly in conjunction with the longer-living second-generation ruthenium-based catalysts, such as Ru-2 and Ru-4.67 3.6. Ethylene Removal To Prevent Catalyst Decomposition and Reduce Undesired Reaction Pathways. Ethylene, the byproduct of RCM reactions, is the least sterically hindered and most reactive alkene in olefin metathesis reactions. According to studies by the Piers group, ethylene has a comparable or even much higher rate of reaction with ruthenium olefin metathesis catalysts than the RCM substrate.68 The removal of ethylene from the reaction mixture therefore accelerates the conversion of the starting diene, although in a nonselective fashion, as the rates of both intramolecular and intermolecular reactions are increased by the removal of ethylene. The concentration of ethylene also affects the concentration of the more vulnerable ruthenium methylidene complexes (e.g., VI in Scheme 2).19,22,69 After one turnover, methylidene complexes are expected to react with another molecule of diene substrate to re-enter the catalytic cycle. In the presence of ethylene, however, they react preferentially with ethylene either to generate ruthenacyclobutane70 or to undergo a nonproductive degenerate metathesis pathway.71 To reduce the cumulative effect of ethylene, which decreases metathesis productivity, RCM reactions are often carried out at elevated temperatures and under an inert atmosphere. The removal of ethylene is often effective because the solubility of ethylene in organic solvents is generally low at elevated temperatures.72 A more efficient way to remove ethylene completely during RCM is by sparging the reaction I



Review

Scheme 9. Removal of Ethylene To Facilitate RCM Reactions

Scheme 10. Ethylene-Induced Catalyst Decomposition Results in Undesired Reaction Pathways

mixture with a stream of inert gas.73 Therefore, degassing has become a routine operation in large-scale RCM reactions, as removal of ethylene from the solution is requisite to achieve high conversion. For instance, an RCM reaction was executed at the kilogram scale to prepare macrocycle 45 for use in the synthesis of ciluprevir (Scheme 9a).3 Toluene was used instead of DCM so that the reaction temperature could be set at 80 °C to obtain a higher reaction rate. This was the maximum reaction temperature for the transformation, as 90 °C would result in considerable exothermic decomposition of both the diene and the macrocyclic product. The solvent was initially degassed until the concentration of oxygen was below 1 mg/L. The degassing operation was continued during the entire reaction period (4−9 h) to remove the ethylene byproduct from the solution, which was proven necessary to achieve high conversion. The operation was carried out by passing a stream of nitrogen (100 L/h) through the reaction mixture. As the active catalyst was not very stable during the whole reaction course,74 the solid catalyst was added in three equal portions over 2 h to compensate for catalyst decomposition pathways. High dilution (118 L of toluene/kg of diene, or 0.011 M) was again necessary to avoid intermolecular cross-metathesis to

form dimers and oligomers. It is important to note that toluene was treated with aqueous HCl to remove the morpholine before use, since morpholine caused catalyst inhibition and impurity formation (see the discussion of control of input impurities in section 3.7). Another example of ethylene removal is presented in the synthesis of macrocycle 47, which is an intermediate for danoprevir, an HCV NS3/4A protease inhibitor developed by Roche.7 The RCM reaction was performed under vacuum (P = 0.26 bar) at 60−70 °C in order to remove ethylene and drive the reaction to completion (Scheme 9b). It is worth noting that the conformational restraint imposed by the cyclopropane and the N-benzoyl group allowed the RCM reaction to be executed at a high diene concentration of 8 wt % (ca. 0.1 M). Several penta- or hexacoordinated Ru catalysts were developed and displayed excellent catalytic activity and selectivity toward RCM. The optimal catalyst Ru-8 allowed the catalyst loading to be reduced to a remarkable 0.05 mol %. Besides suppression of the desired RCM, ethylene has been found to induce catalyst decomposition and to be responsible for undesired reaction pathways. According to the theoretical and experimental observations from van Rensburg and coworkers, β-hydride transfer from the aforementioned ruthJ



Review

Scheme 11. Olefin Isomerization Induced by a Ruthenium Hydride Complex

Table 4. Optimization of the RCM Reaction in the Synthesis of Vaniprevir To Prevent Ru Catalyst Degradation or Suppress Ruthenium Hydride Formation

entry

catalyst loading (mol %)

reaction temp. (°C)

conc. (mL/g of 13)

1 2 3 4 5 6 7 8 9

1 1 1 0.5 0.2 0.2 0.2 0.2 0.2

60 60 70 70 70 100 100 100 100

50 30 20 20 20 20 20 13.5 13.5

additive − − − 10 10 10 10 10 10

mol mol mol mol mol mol

% % % % % %

50 50 50 50 50 50

operation mode

yield of 12 (%)

yield of 49 (%)

− − − − − − N2 sparging N2 sparging N2 sparging and slow addition of 13

82 61 62 72 72 84 88 78 91

Ring-Closing Metathesis in Pharmaceutical Development

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