Microwaves

Jonathan D. Moseley

JONATHAN D. MOSELEY

Microwave synthesis in process chemistry

Method, scale and scope
ABSTRACT This review will present the current state of commercial microwave scale-up instruments for organic synthesis in process chemistry within the context of the pharmaceutical industry. The different methods of scale-up will be discussed and the effect this has on the scale achievable. Representative examples of pharmaceutical chemistry will be given for each instrument type. Other applications of how microwave heating can aid the process development chemist will also be presented briefly. INTRODUCTION Microwave assisted organic synthesis has established itself as the method of choice in many pharmaceutical companies for initial drug discovery synthesis. The features of small scale, fast reaction time and convenient automation marry well with combinatorial and library synthesis techniques and have provided a step change in drug discovery programmes (1). The other advantages of microwave heating, such as cleaner reaction profiles and higher yields, often facilitated by access to super-heated solvents, will be familiar to many and have been reported elsewhere (1-3). Many of these and other advantages are also of interest to process chemists. The first significant attempts to scale up microwave chemistry in organic synthesis were conducted by Strauss in the 1990s (4). However, a limiting factor for scale-up is the penetration depth of the microwave field, which is only a few centimetres in most solvents (5). This has so far limited attempts to scale up microwave synthesis in batch reactors beyond semi-prep scale (6). Consequently, most surveys have concluded that a continuous flow system will be required for pilot/production scales (7) and many prototypical small-scale continuous flow microwave reactors have been reported in recent years (8). However, these are also not without issues within a pharmaceutical chemistry context as will be discussed below. More recently, the use of alternative microwave frequencies, which can have either greater or lesser penetration depths through solvents, have been investigated (9). The option to change the frequency may provide an alternative solution to the problem of microwave scale-up. It should also be noted that many other industries, including ceramics and mining, successfully use microwave heating on a large scale. However, these applications do not generally require the controlled heating of delicate organic molecules whilst suspended in relatively low boiling and often flammable solvents. This review covers our own experiences in the use of microwave chemistry within pharmaceutical process chemistry for both scale-up and other applications, and is based on a recent conference presentation (10). We have concentrated our investigations on commercially available scale-up microwave reactors (11), which have been reviewed collectively by Kappe (12), Leadbeater (6) and ourselves (13). METHODS OF SCALE-UP A diverse range of instruments is available, each with different operating principles and achievable scales, since the scale cannot be easily separated from the method used. Aside from the need for an advantage over competitors patents, this indicates to us that there is currently no generally accepted solution to the problem of microwave scale-up. The commercial approaches taken can be summarised as follows: Scale-up in multiple sealed vessels Scale-up in one large sealed vessel Scale-up in one large open vessel Scale-up by continuous flow Scale-up by automated stop-flow Scale-up in multiple sealed vessels is the obvious extension from the use of small scale microwave reactors. These multiple vessel microwave reactors typically have 6-16 sealed vessels of 75-300 mL individual volume, although multiple configurations are possible in some reactors. This gives typically ~1 L total processing volume per cycle, as exemplified by the Anton Paar Synthos 3000 (Figure 1). Whilst these reactors can exactly replicate small scale microwave experiments, and

Figure 1. Anton Paar Synthos 3000 multiple sealed vessel microwave reactor.

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can readily produce a hundred grams of product (14), they are tedious to charge and discharge if larger quantities are required (and none are as yet integrated with an automation system). Using a single large reaction vessel (up to 3 L in the Milestone Ultraclave) appears to avoid this problem, whilst allowing the continued use of superheated solvents. But larger vessels require more safety features to mitigate the concerns of larger pressurised vessels, which add to the size and the cost of such reactors. Furthermore, since the surface area-to-volume ratio drops with increasing volume, and most microwave reactors have poor cooling capabilities (because microwave transparent materials for vessel walls are generally thermal insulators such as ceramic, glass and PTFE), the reaction cycle time increases so that the benefits of scale-up may be compromised. An alternative is to use an open vessel system, as exemplified by the CEM MARS (Figure 2). Figure 2. CEM MARS microwave reactor Figure 3. Milestone FlowSYNTH continuous (open vessel mode). flow microwave reactor. Standard laboratory glassware up to 5 L can be used in this type of reactor. The lack of pressure means that thin-walled glass vessels can be used with less impact on cooling time. But this is also a drawback since small scale super-heated (autoclave) reaction conditions cannot be repeated on scale-up. Furthermore, microwave penetration depth through the solvent limits the size of the vessel in any case to about 5 L (this limit also affects the sealed vessel systems). To overcome the limited penetration depth issue, a continuous flow system seems an ideal match with the fast reaction times typical of microwave chemistry. A tubular vessel can be completely irradiated with microwaves, and the flow rate adjusted for the required reaction time. As discussed, many prototypical microwave (and non-microwave) continuous flow reactors have been designed and chemistry reported in them. Volume through-puts for continuous flow reactors Figure 4. CEM Voyager SF stop-flow microwave reactor. are always impressive. Of commercial microwave systems, only the Milestone FlowSYNTH exists (Figure 3). However both this and the prototype instruments suffer from the general offers. Changing from batch to continuous flow systems late limitations of continuous flow systems in requiring homogein the development phase may also have regulatory implications neous reaction mixtures in most cases. for a pharmaceutical product. This is a significant drawback in a pharmaceutical context, Lastly, an alternative to continuous flow is available in the where heterogeneous reaction mixtures are often involved CEM Voyager SF stop-flow reactor (Figure 4). This may seem at some point in the majority of reactions, with either solid to incorporate several drawbacks discussed above, namely inputs or products, or transient solids formed during the small vessel size, multiple vessel charges and the need for course of a reaction. homogeneous reaction mixtures. However, the small vessel This commonly leads to blockages and/or poor mixing. allows pressure to be contained in a small instrument and Whilst these problems may be overcome by dilution or facilitates fast cooling times; and automated charging and otherwise modifying the process, this requires time and loses discharging overcomes the multiple charging and manual the advantage that linear scale-up of microwave chemistry handling issues.

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compound required 140C for 10 Homogeneous reaction mixtures are still minutes, and could conveniently be required as for other continuous flow completed in the Synthos 3000, where reactors however. Overall, it will be seen the sealed vessel option was needed from the discussion above that none of to contain the volatile formic acid (bp. these microwave reactors, with the Scheme 1. The Newman-Kwart rearrangement. 100C). exception of the continuous flow varieties, More typical of pharmaceutical reactions is the alkylation is really capable of delivering the throughput of multiple litres reaction to provide the O-allyl ether Claisen precursors per hour required for the pharmaceutical process chemist (Scheme 2). This typically involves two reaction components, working at pilot scale or above. Continuous flow reactors can an insoluble inorganic base (K2CO3 in this case) and a achieve this, but are limited to homogeneous solutions. Batch reactors can process slurries and viscous liquids, but their polar aprotic solvent. The use of high boiling solvents like volume is limited by pressure constraints, and even if they were NMP extends the temperature range so that fast microwave not, the limited penetration depth of microwaves in solvents reaction conditions can be accessed. O-Allyl ether formation would still present a problem. However, scale-up from several in 7 volumes of NMP could be achieved with an allyl chloride hundred grams to kilograms is after just 10 minutes at 150C in the MARS (compared to possible in the currently available typically 18 hours in acetone at 56C). On a 2 L scale, commercial microwave reactors, ~300 g of product could be obtained per reaction, which as discussed below. took typically 1 hour including cooling. This is below the full volume and heating capacity of the reactor so more could be produced. Barnard and Leadbeater have published EXAMPLES several impressive examples on larger scales for alkylation OF SCALE-UP and other reactions in the MARS yielding kilo-scale production per run (21). We have trialled examples of S N Ar reactions are another common two component the Newman-Kwart pharmaceutical reaction and we have performed several rearrangement (NKR) (15) model reactions under conditions similar to the alkylation (Scheme 1) in all the reaction above (Scheme 3). Product yields of 150-300 g microwave reactors discussed can easily be obtained per run in the open vessel reactors Scheme 2. O-Allylether above (13). Kilogram scale like the MARS, giving near kilogram scale quantities per formation, Claisen rearrangeproductivity can be achieved day. However, both this and the alkylation reaction require ment and Benzofuran formation. because this reaction is very multiple reaction components and inorganic base. Charging concentrated. Indeed, we have achieved multi-kilogram to the multiple vessel systems of the MARS, MultiSYNTH and scale throught-puts (4 kg/day) using the FlowSYNTH Synthos 3000 starts to become tedious and would not be continuous flow reactor (16). However, in the open vessel ideal if more than a couple of reaction cycles were required. MARS and MultiSYNTH type reactors this reaction is only Furthermore, the insoluble base precludes their use in any possible for favourable examples (i.e. those with electronof the flow reactors. withdrawing substituents) (17), and even then, only up to The Heck reaction is another versatile reaction much used the solvent boiling point. Disfavoured examples (18) would in pharmaceutical synthesis (22). We have trialled a require the sealed system options of the Synthos 3000 to homogeneous model reaction (Scheme 4) in the sealed vessel reach temperatures of up to 300C. One recent AstraZeneca Synthos, the open vessel MARS and the stop-flow Voyager. example used the XQ-80 A reaction time of 2-10 quartz glass vessel option to minutes at 130-140C in achieve 285C for a dimethylacetamide (DMA) as disfavoured NKR, and was reaction solvent gives high briefly considered for kilogram conversion and isolated yield Scheme 3. Typical SNAr reactions. scale production to support in all cases. A homogeneous a drug project. Charging reaction mixture makes multiple multiple vessels is not restrictive in charging in the Synthos easy, in the this case since a stock solution of single vessel MARS easier, but most starting material can be made and convenient in the stop-flow Voyager easily dispensed into and discharged (19). In total, ~500 batches have from each vessel. now been run in typically 50 batch Scheme 4. Generic Heck reaction. Another high temperature cycles of 7 hrs each, producing ~200 rearrangement that has also been g product per day. Interestingly, the used on AstraZeneca projects is the well-known Claisen conversion gradually degraded over many batches due to rearrangement (19). The 1-naphthyl-subtituted compound the build up of black residues and a Pd mirror on the vessel (Scheme 2) required only 190C and could be converted walls. Cleaning restores good performance, but this does neat in the open vessel MARS; whereas the 4-methoxyphenyl illustrate that even flow systems cannot be run continuously. compound required 240C and the services of the Synthos 3000. The naphthyl example has also been converted in the Voyager stop-flow microwave on 1.0 kg scale to demonstrate FURTHER SCOPE IN SCALE-UP the robustness of the instrument under repeated cycles. Total reaction time was 17 hours with 48 batches performed in Additional areas where microwave chemistry can aid the two equal sequences (20). Very high through-puts could be scale-up functions are as follows: achieved in this case because the reaction is performed neat. Route design and selection Slightly more dilute is the acid-catalysed benzofuran ring Reagent/solvent/catalyst/ligand screening closing reaction, achieved by adding 1-2 volumes of formic Reaction parameter screening acid to the crude Claisen products (Scheme 2). Only a modest Rapid determination of reaction kinetics 100C for 10 minutes is required to convert the 1-naphthyl Lab scale intermediates/impurities supply compound in the MARS, whereas the 4-methoxyphenyl Access to extreme conditions

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of the lab work; and Anton Paar, Biotage, CEM and Milestone for technical support.
REFERENCES AND NOTES
1. 2. C.O. Kappe, A. Stadler, Microwaves in Organic and Medicinal Chemistry, Wiley-VCH, Weinheim (2005). (a) Microwaves in Organic Synthesis, 2 nd Edn. (Ed.; A. Loupy), Wiley-VCH, Weinheim (2006); (b) Microwave Assisted Organic Synthesis, (Eds.: J. P. Tierney, P. Lidstrm), Blackwell, Oxford (2005); (c) B.L. Hayes, Microwave Synthesis: Chemistry at the Speed of Light, CEM, Matthews (2002). (a) C.O. Kappe, Angew. Chem. Int. Ed. 43, pp. 6250-6284 (2004); (b) B.L. Hayes, Aldrichimica Acta 37, pp. 66-76 (2004); (c) M. Nchter, B. Ondruschka et al., Green Chem. 6, pp. 128-141 (2004). B.A. Roberts, C.R. Strauss, Acc. Chem. Res. 38, pp. 653-661 (2005). C. Gabriel, S. Gabriel et al., Chem. Soc. Rev. 27, pp. 213-223 (1998). M.D. Bowman, J.L. Holcomb et al., Org. Process Res. Dev. 12, pp. 41-57 (2008). See relevant sections in references 1-3. For selected examples see:- (a) W.S. Bremner, M.G. Organ, J. Comb. Chem. 9, pp. 14-16 (2007); (b) I.R. Baxendale, M.R. Pitts, Chemistry Today 24(3), pp. 41-45 (2006); (c) M.C. Bagley, R.L. Jenkins et al., J. Org. Chem. 70, pp. 7003-7006 (2005); (d) N.S. Wilson, C.R. Sarko et al., Org. Process Res. Dev. 8, pp. 535-538 (2004); (e) W.-C. Shieh, M. Lozanov et al., Tetrahedron Lett. 44, pp. 6943-6945 (2003); (f) W.-C. Shieh, S. Dell et al., Tetrahedron Lett. 43, pp. 56075609 (2002); (g) B.M. Khadilkar, V.R. Madyar, Org. Process Res. Dev. 5, pp. 452-455 (2001); (h) J. Marquie, G. Salmoria et al., Ind. Eng. Chem. Res. 40, pp. 4485-4490 (2001). (a) S. Horikoshi, T. Hamamura et al., Org. Process Res. Dev. 12, pp. 1089-1093 (2008); (b) S. Horikoshi, S. Iida et al., Org. Process Res. Dev. 12, pp. 257-263 (2008). J.D. Moseley, Microwave Synthesis in Process Chemistry Method, Scale and Scope, Microwave and Flow Chemistry Conference, Zing Conferences, Antigua, 28th-31st January 2009. (a) www.anton-paar.com; (b) www.biotage.com; (c) www.cem.com; (d) www.milestonesrl.com. J.M. Kremsner, A. Stadler et al., Top. Curr. Chem. 266, pp. 233-278 (2006). J.D. Moseley, P. Lenden et al., Org. Process Res. Dev. 12, pp. 30-40 (2008). (a) J. Alczar, G. Diels et al., QSAR Comb. Sci. 23, pp. 906-910 (2004); (b) A. Stadler, B.H. Yousefi et al., Org. Process Res. Dev. 7, pp. 707-716 (2003). G.C. Lloyd-Jones, J.D. Moseley et al., Synthesis, pp. 661-689 (2008). J.D. Moseley, S.J. Lawton, Chimica Oggi/Chemistry Today 25(2), pp. 16-19 (2007). J.D. Moseley, R.F. Sankey et al., Tetrahedron 62, pp. 4685-4689 (2006). J.D. Moseley, P. Lenden, Tetrahedron 63, pp. 4120-4125 (2007). A.M.M. Castro, Chem. Rev. 104, pp. 2939-3002 (2004). J.D. Moseley, E.K. Woodman, Org. Process Res. Dev. 12, pp. 967981 (2008). (a) T.M. Barnard, G.S. Vanier et al., Org. Process Res. Dev. 10, pp. 1233-1237 (2006); (b) N.E. Leadbeater, V.A. Williams et al., Synlett, pp. 2953-2958 (2006); (c) N.E. Leadbeater, V.A. Williams et al., Org. Process Res. Dev. 10, pp. 833-837 (2006). (a) I. Beletskaya, A. Cheprakov, Chem. Rev. 100, pp. 309-3066 (2000); (b) V. Farina, Adv. Synth. Catal. 346, pp. 1553-1582 (2004). T.M. Glasnov, H. Tye et al., Tetrahedron 64, pp. 2035-2041 (2008). N.E. Leadbeater, J.R. Schmink, Tetrahedron 63, pp. 6764-6773 (2007). J.P. Gilday, P. Lenden et al., J. Org. Chem. 73, pp. 3130-3134 (2008). J.D. Moseley, R.L. Woodward, unpublished results. J.M. Kremsner, C.O. Kappe, Eur. J. Org. Chem., pp. 3672-3679 (2005).

Figure 5. Rapid determination of reaction time.

Fast microwave reactions allow new routes to potential new pharmaceuticals to be scouted very quickly. Even if scaleup by this chemistry is not an option, the validity of a reaction sequence may be quickly established, and this has been applied to several AstraZeneca projects. Medicinal chemists are likely to have screened some reagents, solvents, catalysts and ligands in their initial synthesis, but process chemists will want to complete the screen thoroughly in case an improved set of conditions for the preferred substrate can be found. Automated small-scale microwaves are ideal for this type of screening activity (23). They are also useful for screening the parameters of a reaction in more detail once the preferred conditions have been identified (24). So for the alkylation reaction above (Scheme 2), the approximate reaction rate was quickly determined by a series of 10 minute microwave reactions (Figure 5). The approximate equivalents of allyl chloride and base were also determined in this way. A factorial experimental design (DoE) (23) could then be applied if more precise conditions were required, but this too could be quickly determined with an automated small scale microwave reactor. We have also used small scale microwave reactors to aid with reaction understanding, whereby automation enabled multiple reaction time points to be taken to facilitate a reaction kinetics study on the NKR (25). From this data, Arrhenius plots were readily determined, which have both confirmed previous results and presented new challenges. A further study is providing insight into selectivity between multiple SNAr reactions (26). We have also used microwave scaleup reactors to synthesise initial laboratory scale quantities to support development projects before alternative routes have been found. This approach could also be used for the synthesis of related impurities to support analytical development where development of an individual synthesis is time-consuming and unnecessary. Finally, microwave reactors can also be used for accessing extreme conditions of temperature or pressure, for example chemistry in near critical water (27). CONCLUSIONS This review has attempted to present the current state of commercial microwave scale-up instruments for organic synthesis within the pharmaceutical industry. A modest scaleup to kilograms can be achieved in favourable cases and examples have been presented from our own and others work. Scale-up to true pilot plant scale with microwave heating in this context has yet to be achieved however. Most experts believe a continuous flow technology is necessary. Microwave heating may augment or replace more traditional heating technologies in demanding applications in these cases. Aside from scale-up, many other applications of microwave heating can also aid the process development chemist. ACKNOWLEDGEMENTS Thanks to students Ros Sankey, Phil Lenden, Anthony Thomson, Emily Woodman and Jameel Marafie for performing much

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JONATHAN D. MOSELEY AstraZeneca Process Research and Development Avlon Works, Severn Road, Hallen Bristol, BS10 7ZE, United Kingdom

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