As Published in LabPlus international - April / May 2003

Only 3 years ago, microwave synthesiswas not a meaningful technology formost organic chemists. Spurred by earlyreports of ultra-fast synthesis usingmicrowave irradiation (reactions arecompleted in minutes compared to hoursand days), some adventurous chemistshad attempted to apply domesticmicrowave ovens to organic synthesis,only to find, at best, unpredictable syn-thesis results, and at worst, themselvescleaning up the lab after an unexpectedexplosion.

Domestic and many industrialmicrowave ovens were not designed torun chemical reactions, in much the sameway as a mobile telephone, albeit amicrowave transmitter, was not designedto warm up food. A multi-mode ovenprovides an uneven microwave field den-sity (Figure 1), which is inadequate forthe task of chemical synthesis.

The first purpose-built microwave syn-thesiser was launched in 2000. Thisdevice was designed to produce a uni-form microwave field, regardless of thecontent of the vessel, with typical lab-scale samples: between 0.5 ml and 5 ml.Equipped to monitor and control thetemperature of the reaction, and to safe-guard against explosions by substantial

safety mechanisms, this microwave syn-thesiser could produce ultra-fast (reac-tions taking typically 5 minutes), highlyreproducible and safe synthesis results.

Reactions are more reproducible whenheated by microwaves largely because theheating process is uniform and highlycontrolled (Figure 3). In addition, thereaction temperature is accurately moni-tored and controlled.

In contrast to heating by conventionalmeans, microwave irradiation raises thetemperature in the reaction volume

simultaneously, without interventionthrough the vessel wall (Figure 4). Thismeans that synthesis proceeds uniformlythroughout the reaction vessel, reachingcompletion simultaneously. This effectalso influences the general scalability ofreactions as an identical temperatureprofile can be achieved regardless of thevolume of the vessel.

Productive, reproduciblechemistry3 years on from the introduction of thefirst commercial microwave synthesiser,regular users of the technique are report-ing that up to 40% of all explorative

chemistry is now being per-formed in this way, and esti-mates suggest that more than10,000 microwave reactionsare run per week. Many ofthese users are in the phar-maceutical and biotechindustries. Figure 5 shows atypical modern microwavesynthesiser, with sampletransfer facilities to eliminatethe tedium of manuallychanging vials every 5 min-utes. Microwave-assisted syn-thesis is well on its way tobecoming a cornerstone ofmodern chemistry develop-ment.Microwave-assisted synthesis

is, in many ways, superior to traditionalheating. The ability to elevate the temper-ature of a reaction well above the boilingpoint of the solvent increases the speed ofreactions by a factor of 10-1,000.Reactions are thus completed in minutesor even seconds. Yields are generallyhigher and the technique may provide ameans of synthesising compounds that isnot available conventionally.

Microwave Synthesis: a new wave ofsynthetic organic chemistry

Microwave-assisted synthesis is set to change organicchemistry for good. The technology is generally applica-ble to syntheses in medicinal and combinatorial chem-istry, and compared to conventional methods offersenhanced speed, reproducibilty and scalability. Thistechnique solves many of the challenges currently fac-ing pharmaceutical chemists and todays easy-to-useinstrumentation, integrated robotics and verified synthe-sis methods are designed to provide a complete labsolution.

Figure 1. Microwave field in a domestic microwaveoven, showing the typical uneven pattern of hot spots(shown here in purple) and cold spots.

by Robert England

CHEMICAL SYNTHESIS

As Published in LabPlus international - April / May 2003

Pharmacuetical lead opti-misationThe speed of microwave synthesis is idealfor developing compounds in the leadoptimisation phase of pharmaceuticaldevelopment. Here, synthetic chemistsapply diverse synthesis methods iterative-ly to develop candidate drugs from leadcompounds. The fast reaction times thatmicrowave synthesis provides give anideal response time for chemists to workout new chemistries and develop propri-etary compounds.

Reaction times are incredibly short, thusa reaction procedure can be fully opti-mised in an hour, and the scope of thereaction can then be tested with a diverseset of substrates in the following hour. Afully optimised procedure and a range ofproducts is produced in the time it takesto run a single conventional reaction.

Knowledge bases formicrowave synthesisFrom the outset, it was clear that thereproducibility and speed of microwave-assisted synthesis would be an ideal foun-dation on which to build a knowledgebase for organic synthesis. Speed wouldcontribute to the rapid development of

methods, and reproducibility is essentialto make the data worthwhile in some-body else's hands. A database of repro-ducible and, as mentioned earlier,scalable synthesis methods was previous-ly unimaginable in organic chemistry.

There is also a general need for a knowl-edge base of microwave synthesis meth-ods because chemists need a referencesource to get them started with this tech-nology. Microwave synthesis imposes asufficiently different set of requirementscompared to traditional synthesis methods(e.g. considerations of the microwave-

absorbing characteristics of solvents;optimisation of reagents to work at ele-vated temperatures; or even the ability torun chemistry in water), that to reallytake advantage of the technique, new syn-thetic methods are warranted.

To address this, the Personal Chemistrycompany has developed EmrysPathFinder, a database of verified synthe-sis methods directed at addressing theneeds of medicinal chemistry. The com-pany has also developed a knowledgemanagement system for pharma andbiotech companies, Coherent Synthesis,which allows researchers to develop andshare their own methods. This manage-ment system allows pharmaceutical R&Ddepartments to immediately reap theproductivity benefits of microwave syn-thesis, and to efficiently apply the knowl-edge to shortcut future developmentprojects by re-application of the rapidlyaccumulated chemistry knowledge.

Furthermore, Personal Chemistry hasdeveloped 11 reaction kits for commontransformations, containing pre-dis-pensed chemicals and optimised meth-ods to further improve the quality andproductivity of chemistry development.

Figure 2. The Single-Mode Resonator design generates an even heating pattern in a lab-scalesized reaction vessel, leading to a high degree of synthesis reproducibility.

Figure 3. Microwave irradiation can generate an "ideal" temperature profile, allowingreactions to be initiated and quenched efficiently and reproducibly.

CHEMICAL SYNTHESIS

As Published in LabPlus international - April / May 2003

Coherent synthesisThe short definition of Coherent Synthesis isknowledge-based microwave synthesis for leadcompound development. This system captures thesynergy from ultra-fast and highly reproducibleorganic synthesis, verified methods, automatedknowledge accumulation, and the efficiency gainedfrom a software-based chemistry workflow plat-form. The result is a major boost in both qualityand productivity at every stage of chemistry devel-opment projects. In May 2002, more than 3,000fully optimised, verified and robust methods basedon microwave synthesis were released. These canbe searched from every chemist's desktop comput-er to support lead compound development.

Most of the methods in the database were devel-oped by the company directly, but they have alsoreceived significant contributions from a scientificpartnership program, which includes Steven Ley (CambridgeUniversity, UK), Mark Bradley (Southampton University, UK)and Barry Sharpless (Scripps Institute, La Jolla, USA). Themethods include everything from "textbook" chemistry toinnovative means of synthesising heterocyclic libraries. Theshort turnaround time that the verified methods provide, incombination with the microwave technology and levels ofautomation available, means that compounds and libraries canbe synthesised on demand.

All of the top 20 pharma and biotech companies have beenquick to invest in microwave technology and most of them haveseveral knowledge-sharing systems at sites all over the globe.Many of these companies are now using Coherent Synthesis ona regular basis, and would like it to become a global chemistryknowledge sharing system. As the systems were originally basedon industry standards like Oracle and Accelrys' AccordChemistry Cartridge, this future development is possible.

SummaryOnly a year back, one of the major objections to microwavesynthesis was that there weren't any solutions to scale-up thechemistry - it was a dead end. Further investigations into thisissue have shown that the opposite is true - that scalability isactually one of the technology's major strengths. The systemsdescribed above give similar conditions over orders of magni-tude of volume. Thus if it is possible to synthesise 10 mg of acompound in Personal Chemistry’s instrument, it is almosttrivial to synthesise 100 g. Therefore the difficulties that werepreviously experienced when trying to convert a benchtopmethod into a large scale operation are avoided. This spring, the

Personal Chemistry company is launching 2 new scale-up prod-ucts and microwave chemistry synthesis services to serve cus-tomer’s scale-up needs.

The authorRobert A. England, Director, Strategic Marketing &Communication, Personal Chemistry AB, Kungsgatan 76,SE-753 18 Uppsala, Sweden.Tel. +46 18 489 9069, Fax: +46 18 489 9200 Email: robert.england@personalchemistry.comwww.personalchemistry.com

Figure 5. Chemist working with Emrys Optimizer

Figure 4. The temperature profile after 60 seconds as affected by microwave irra-diation (left) compared to treatment in an oil-bath (right). Microwave irradia-tion raises the temperature of the whole reaction volume simultaneously, whereasin the oil heated tube, the reaction mixture in contact with the vessel wall is heat-ed first.Temperature scale in Kelvin. "0" on the vertical scale indicates the posi-tion of the meniscus.

CHEMICAL SYNTHESIS