Dr C Oliver Kappe is AssociateProfessor at the Institute of Chemistry

at Karl-Franzens-Universität Graz,Austria, where he conducts research

on microwave synthesis andcombinatorial chemistry. He has

co-authored more than 100scientific publications devoted tosynthetic organic chemistry. Most of

his current work is related tointerfacing microwave chemistrywith modern synthetic methodsusing state-of-the-art microwavereactor technology. Dr Kappe’s

post-doctoral work (1993–1996)was in the field of synthetic and

physical organic chemistry at EmoryUniversity, Atlanta, and at the

University of Queensland, Brisbane,Australia. He obtained his BSc andPhD (1992) in Organic Chemistry

from the University of Graz.

a report by

D r C O l i v e r K a pp e

Associate Professor, Institute of Chemistry, Karl-Franzens-Universität Graz

Ba c k g r o u nd

Improving drug research and development (R&D)productivity is one of the greatest tasks facing the pharmaceutical industry. Many of the toppharmaceutical companies need to deliver innovativeproducts in order to maintain top-line sales growth.In the next 10 years, the pharmaceutical industry willsee many patents of drugs, currently generating someUS$91 billion in sales, expire. In order to remaincompetitive, pharma companies need to pursuestrategies that will offset the sales decline and seerobust growth and shareholder value.

The top pharmaceutical companies are now lookingfor products that can generate at least US$1.6 toUS$2 billion of new sales every single year.1 Thatequates to up to four blockbusters – products withsales of between 500 million and one billion – a year.At the same time, the cost of developing a drug todayis approximately US$700 million, and the US Foodand Drug Administration (FDA) estimates theaverage development time still to be approximately10 to 15 years. Both cost and development time areunacceptably high to maintain an industry growthrate of 10%.

The impact of genomics and proteomics isadditionally creating an explosion in the number ofdrug targets. Today’s drug therapies are based solelyon approximately 500 biological targets, while, in 10years’ time, the number of targets could well reach10,000. In order to identify more potential drugcandidates for all of these targets, pharmaceuticalcompanies have made major investments in high-throughput technologies for genomic and proteomicresearch, combinatorial chemistry and biologicalscreening. However, lead compound optimisation

and medicinal chemistry remain the bottlenecks inthe drug discovery process. Developing chemicalcompounds with the desired biological properties istime-consuming and expensive. Consequently,increasing interest is being directed towardstechnologies that allow more rapid synthesis andscreening of chemical substances to identifycompounds with functional qualities.

M i c r owa v e S y n t h e s i s

A new technique that is set to revolutionise synthesishas recently moved to the forefront of chemicalresearch – microwave-assisted organic synthesis(MAOS).2–4 While fire is now rarely used in syntheticchemistry, it was not until Robert von Bunseninvented the burner that the energy from this heatsource could be applied to a reaction vessel in afocused manner. The Bunsen burner was latersuperseded by the isomantle, oil bath or hotplate as asource of applying heat to a chemical reaction.

Microwave technology has been used in chemistrysince the late 1970s, but it has only been implementedin organic synthesis since the mid 1980s. The slowuptake of the technology has been attributed to itsinitial lack of controllability and reproducibility,coupled with a general lack of understanding of thebasics of microwave dielectric heating. However,since the late 1990s, the number of publicationsrelated to MAOS has increased dramatically to a pointwhere it might be assumed that, in a few years, mostchemists will probably use quick bursts of microwaveenergy to heat and drive chemical reactions.4,5

As of 2003, many of the top pharmaceutical, agro-chemical and biotechnology companies were alreadyusing MAOS as a forefront methodology for library

Microwave-enhanced Chemis t r y – Enab l ing Techno logy Revo lu t ion i s ingOrgan ic Synthes i s and Drug Di scover y

28

Drug Development

B U S I N E S S B R I E F I N G : P H A R M A O U T S O U R C I N G

1. Nitin Naik, “Brave New Biotechnology World Revisited”, Business Briefing: Future Drug Discovery 2002, WorldMarkets Research Centre Ltd: London, October 2002, pp. 20–25.

2. D Adam, “Microwave Chemistry – Out of the Kitchen”, Nature, 421 (2003), pp. 571–572.3. For more information on microwave synthesis and equipment, see http://www.maos.net4. P Lidström, J Tierney, B Wathey and J Westman, “Microwave Assisted Organic Synthesis – A Review”, Tetrahedron,

57 (2001), pp. 9,225–9,283.5. B Hayes, Microwave Synthesis – Chemistry at the Speed of Light, CEM Publishing: Matthews, North Carolina,

2002.

Kappe_edit.qxd 19/1/04 2:36 pm Page 28

Organix, a privately held synthetic organic chemistry custom synthesis and contract research company that conducts research as well as preparation of organic and inorganic molecules at themilligram to subkilogram level.

When in-house organic chemistry facilities are not an option...

Choose a company that provides:

• Custom Synthesis

• Contract Research & Development

• Fixed Price and FTE Projects

• Optimization of Synthetic Methods

• Structure Activity Relationship Studies

• Discovery and Synthesis of New

Chemical Entities

• Characterization of components of

complex organic mixtures

• Preparation from milligram to subkilogram

quantities of compounds

Discover that outsourcing to an independent contract research organization (CRO) provides the following benefits:

• Accessibility to cost effective and efficient resynthesis

and custom synthesis

• Expertise to design and develop new compounds, novel

analogs and new patentable intellectual property

• Confidentiality of proprietary information

• A modern facility designed specially for organic chemistry

On Time — On Price — On Budget

Woburn, Massachusetts 01801 USA (20 minutes north of Boston)Phone: (781) 932.4142Fax: (781) 933.6695Email: organix@organixinc.com

www.organixinc.com

Organix_ad.qxd 15/1/04 3:59 pm Page 29

B U S I N E S S B R I E F I N G : P H A R M A O U T S O U R C I N G

30

Drug Development

synthesis and lead optimisation as they realise theability of this enabling technology to speed chemicalreactions. Not only are microwaves sometimes able toreduce chemical reaction times from hours tominutes, but they are also known to reduce sidereactions, increase yields and improve reproducibility.

T h e o r y a n d E q u i pmen t

Almost any type of organic reaction requiringheating or thermal conditions can be performedusing microwave radiation. Microwave dielectricheating is dependent on the ability of a solvent ormatrix to absorb microwave energy and to convert itinto heat.4,5 The matrix absorbs the radiation via twomechanisms: dipole polarisation and conduction.

When irradiated at microwave frequencies, the ionsor dipole of the sample align in the applied electricfield. As the applied field oscillates, the dipole or ionfield attempts to realign itself with the alternatingelectric field and, in the process, energy is lost in theform of heat through molecular friction anddielectric loss. The amount of heat generated by thisprocess is directly related to the ability of the matrixto align itself with the frequency of the applied field.If the dipole does not have time to realign, orreorients too quickly with the applied field, noheating occurs. The allocated microwave frequencyof 2.45GHz used in all commercial systems liesbetween these two extremes and gives the moleculardipole time to align in the field, but not to follow thealternating field precisely.

Microwave irradiation produces efficient internalheating (in situ heating), resulting in even heatingthroughout the sample, as compared with the wallheat transfer that occurs when an oil bath is appliedas an energy source. Consequently, the tendency forthe initiation of boiling is reduced, and superheatingabove the boiling point of the solvent is possible evenat atmospheric pressure. Superheating can begenerated rapidly in closed microwave-transparentvessels to temperatures as high as 100°C above thenormal boiling point of a particular solvent.

It is this combination of rapid microwave heatingand sealed vessel technology that is responsible formost of the observed rate enhancements seen in

MAOS, based on the well-known ‘rule of thumb’that, for every 10°C increase in temperature, therate of the reaction is approximately doubled. It ispossible, however, that macroscopic or microscopichotspots resulting from selective heating of specificreagents or catalysts can develop, leading to even

faster conversions and the realisation of chemistriesthat cannot be conducted by conventional heating.

Evidently, more research is required to investigatethe underlying principles of this heating method.Regardless of the exact origin of the observed rate enhancements, microwave synthesis isextremely efficient and applicable to a broad rangeof practical synthesis.

Although most of the early pioneering experimentsin MAOS were carried out in domestic kitchenmicrowave ovens, the current trend clearly is to usededicated instruments for chemical synthesis.2–4 Mostof today’s commercially available microwave reactorsfeature built-in magnetic stirrers, direct temperaturecontrol of the reaction mixture with the aid of fibreoptic probes or infrared sensors and software thatenables online temperature/pressure control byregulation of microwave output power. Since 2003,suppliers of microwave instrumentation for organicsynthesis have also moved towards combinatorial/high-throughput platforms, addressing the needs ofthe drug discovery industry.3

Currently, two different philosophies with respect tomicrowave reactor design are emerging: multimodeand monomode reactors.4,5 In the so-called multimodeinstruments, the microwaves that enter the cavity arebeing reflected by the walls and the load over thetypically large cavity. A mode stirrer ensures that thefield distribution is as homogeneous as possible. In themuch smaller monomode or single-mode cavities,only one mode is present and the electromagneticirradiation is focused directly through an accuratelydesigned wave guide onto the reaction vessel mountedin a fixed distance from the radiation source.

For high-throughput applications, the key differencebetween the two types of reactor systems is that,whereas in multimode cavities several reactionvessels can be irradiated simultaneously in multi-

Regardless of the exact origin of the observed rate

enhancements, microwave synthesis is extremely efficient and

applicable to a broad range of practical synthesis.

Kappe_edit.qxd 19/1/04 2:37 pm Page 30

Pharmacore

• An Expanding Collection of novel molecularbuilding blocks

• Custom organic synthesis, flexible and rapidresponse

• cGMP Scale-up

PharmaCore is a leader in the development ofmolecular building blocks for small molecule drugdiscovery.

PharmaCore’s NEW 2003 catalogue featuresapproximately 400 drug-like building blocks withover 250 new compounds.

Email or visit our website for your copy

USA

Tel: +1 336 841 5250 Web: www.pharmacore.comFax: +1 336 841 5350 Email: info@pharmacore.com

Europe

Tel/Fax: +44 (0)1353 687900Mobile: +44 (0)7966 420820Email: mfordham@pharmacore.com

Leading Force in Structure and Reaction Handling and Retrieval

■ Structure and retrieval search engine■ Reaction Classification Algorithm CLASSIFY■ Reaction Mapping IC-MAP■ Web Search System - Electronic Versions of Major Reference Works (MRW), CAC(Springer),

e-EROS (John Wiley), Science of Synthesis (Thieme)■ One of the largest structure and reaction databases worldwide SPRESIweb

(Source: VINITI / InfoChem)

■ 4.5 million molecules, 3.5 million reactions from 380,000 references and 98,000 patents

■ Started 1974■ Open architecture enables individual links

InfoChem Gesellschaft für chemische Information mbH Landsberger Straße 408 D-81241 München www.infochem.de

pharmout_31_hr.qxd 15/1/04 4:41 pm Page 31

vessel rotors (parallel synthesis), in monomodesystems only one vessel can be irradiated at a time.In the latter case, high throughput can be achievedby integrated robotics that move individual reactionvessels in and out of the microwave cavity(automated sequential synthesis).

P r o du c t i v i t y I n c r e a s e – T ime i s Mon e y

The bottleneck of parallel synthesis is typicallyoptimisation of reaction conditions to afford thedesired products in suitable yields and purities. Sincemany reaction sequences require a heating step forextended time periods, these optimisations are oftendifficult and time-consuming.

Microwave-assisted heating has been shown to be aninvaluable optimisation method since it reducesreaction times dramatically, typically from days orhours to minutes or seconds.6 Many reactionparameters can be evaluated in a few days to optimisethe desired chemistry. Compound libraries can thenbe synthesised rapidly using the new technology,either in a parallel or sequential mode.

Several large pharmaceutical companies have reporteddramatic productivity increases in switching fromconventional synthesis to MAOS.7–12 Although theinitial investment costs are considerable, the drama-tically increased efficiency of the microwave approachallows a return of investment in a short timespan. Thishas prompted several pharmaceutical companies toinstall multiple microwave reactors in their R&Dlaboratories, in some cases even eliminating oil bathsand heating mantles from their laboratories.

The success stories of MAOS in the drug discoveryprocess are manifold and have been documented inseveral articles involving both target and leaddiscovery, lead optimisation and drug develop-ment.6–12 With the most recent advances in reactortechnologies such as continuous-flow microwavesystems, even process chemists are now taking MAOS

seriously. Chemistry applications have ranged fromconventional solution phase synthesis to protocolsinvolving polymer-supported reagents or scavengers,in addition to solid or fluorous phase techniques.6–12

Most recently, microwaves have also been used tospeed up biochemical processes such as polymerasechain reaction or enzyme-mediated protein mapping.The full scope and potential of this technology maynot yet have been realised.

Ob s t a c l e s t o A c c e p t a n c e o f t h eT e c h n o l o g y

Given the advantages of microwave synthesis, itmight be surprising that not everybody is using it.One of the possible reasons for this could be mentalinertia, as the use of this new technology requires achange in the chemist’s mindset, abandoning thetraditionally favoured tools of the trade such asheating mantles, oil baths or hotplates forsomething different.

Another factor that is certainly holding the field backis prices. The least expensive of the new generation ofmicrowave reactors currently sells for aboutUS$20,000, which is beyond the buying power ofmany laboratories. More elaborate systems gearedtowards the drug discovery industry that haveintegrated automation and liquid handling capabilities,database and electronic laboratory functionalities or anadded scale-up option involving continuous flow cellsare considerably more expensive. Despite this fact, it isclear that microwave synthesis is an enablingtechnology that is here to stay. In five to 10 years, weare probably going to see a microwave reactor in everyacademic and industrial laboratory. They will trulybecome the Bunsen burners of the 21st century. Toquote French novelist and poet Victor Hugo:

“There is one thing stronger than all the armies inthe world, and that is an idea whose time has come.”

The time for microwave synthesis certainly has arrived. ■

B U S I N E S S B R I E F I N G : P H A R M A O U T S O U R C I N G

32

Drug Development

6. M Larhed and A Hallberg, “Microwave-assisted High Speed Chemistry: A New Technique in Drug Discovery”, DrugDiscovery Today, 6 (2001), pp. 406–416.

7. D Bradley, “They Nuke the Thing for Synthesis. In Combinatorial Chemistry, the New Wave is Micro”, Modern DrugDiscovery, 4 (2001), pp. 32–34 and 36.

8. G Roth and C Sarko, “Microwave Energy Speeds Organic Synthesis”, Drug Discovery and Development, September2001, pp. 57–58.

9. B Wathey, J Tierney, P Lidström and J Westman, “The Impact of Microwave-assisted Organic Chemistry on DrugDiscovery”, Drug Discovery Today, 7 (2002), pp. 373–380.

10.C O Kappe, “High-speed Combinatorial Synthesis Utilizing Microwave Irradiation”, Current Opinion in ChemicalBiology, 6 (2002), pp. 314–320.

11.G Dutton, “Employing Microwaves to Accelerate Synthesis”, Genetic Engineering News, 22 (2002), pp. 12, 15 and17.

12.K J Watkins, “Up Close & Personal – Chemistry, That Is. Sweden’s Personal Chemistry Uses Automated MicrowaveSystems to Speed Drug Development”, Chemical and Engineering News, 80 (2002) 6, pp. 17–18.

Kappe_edit.qxd 19/1/04 2:37 pm Page 32