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How soon is now?IT systems forREACH

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How soon is now?IT systems forREACH

Take theleadActing as leadregistrant

Catalysts ... Mixing & separation technology... Cosmetics & personal care ... Thailandspecial report ... Chemspec India preview

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MARCH 2010Volume 30 No. 03

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Volume 30 No. 03

Regulars

Editor’s letter 4

News 6

Forthcoming events 50

Catalysts

Organozinc halides in catalysis 12Dr Andreas Leitner of BASF looks at the use of organozinc halides as stable functionalised nucleophiles for cross-coupling reactions

Progress in gold catalysis 15Antony Wright of Strem Chemicals describes emerging patterns in the use of gold catalysts in organic synthesis

Polymer-immobilised precious metal catalysts in synthesis 18Dr Pete Jackson of Reaxa considers some of the latest developments

Knochel-Hauser bases for selective deprotonation reactions 20Dr Christoph Krinninger of Chemetall presents new bases

Scavenging for palladium 22Pasi Kauppinen and Stephanie Phillips of Johnson Matthey illustrate the use of Smopex scavengers in separating palladium

Mixing & separation technology

Modern mixing methods 24Companies are developing advanced technologies that reduce energy consumption and increase mixing efficiency

UPLC in the lab 26Jim Hillier of Tepnel Pharmaceutical Services looks at the emergence of UPLC technology and what it can offer to laboratory processes

Cosmetics & personal care

Smooth operators 28What will the leading suppliers of silicones be showing at In-Cosmetics?

Twenty years of beauty 30In-Cosmetics returns to Paris this April. SCM takes a look ahead

REACH implementation

In the driving seat 31Riku Rinta-Jouppi of REACHLaw looks at the issues for lead registrants

Sharing your suites 34Using the right data sharing IT system is crucial to successful registration inDecember, says Malcolm Pollard of Baytouch

REACH supply chain communication: Devil in the substance 38REACH requires manufacturers to learn much more about their materials, says Jean-Grégoire Manoukian of Atrion International

Navigating through REACH 40Marc Kiener and Michael Botzian of Likedeelers introduce Fit4REACH

REACH implementation = information: What and how? 42Substance Information Management Systems are vital to company strategies to implement REACH, says Dijana Spasojevic of Trasys

Thailand special report

The Thais that bind 45Global Business Reports prepared this report on the Thai chemicals sector

Chemspec India preview

Full steam ahead for Mumbai 48The sixth Chemspec India takes place in April. We take a look ahead

Speciality Chemicals Magazine March 2010 3


48Indian summer

45Old school Thai

30Pretty big

In the May issue of Speciality ChemicalsMagazine

• Pharmaceuticalintermediates• Reactor technology• Biocides• Green chemistry• Chemspec Europe 2010preview & show edition

EDITORIAL:.

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Speciality Chemicals Magazine (ISSN 0262-2262)(USPS No: 021-883) is published in January, March,May, July, September & November by Quartz BusinessMedia Ltd, and distributed in the US by DSW, 75Aberdeen Road, Emigsville PA 17318-0437. Periodicalspostage paid at Emigsville, PA.

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Contents.qxp 10/3/10 09:47 Page 3

Aweek in San Francisco is always an attractive prospect inthe depths of a miserable winter and now that InformexUSA has taken place there three times in four years, thereis an enjoyable ritual to it all. Cable car ride? Check. Chinese New

Year celebrations in Chinaown? Check. Clam chowder in sour-

dough by the bay? Check. Fog foiling plans to cycle over Golden

Gate Bridge? Check. But there was also work to do.

(You may know, incidentally, that my employer, as organiser of

the Chemspec shows, is now in a direct competitive situation with

UBM, the organiser of the CPhI and Informex events, because of

the launch of Chemspec USA in Philadelphia next year. This does

not affect my commitment to fair coverage of UBM’s events.)

The number of attendees at Informex USA this year was on a

par with last year, according to UBM, and the area covered by

stands at the Moscone South was also about the same. The gen-

eral feeling was considerably better than in 2009. It could hardly

have been worse

Last February, the chemicals industry as a whole was reeling

after the worst slump in modern times and fine chemicals were

not spared. The sector was already suffering then and the early

company results for 2009 suggest that 1H was a very rough time

for many, albeit that there was something of a recovery in 2H.

“What has changed since Informex 2009” asked Gilles Cottier,

president of SAFC Pharma, rhetorically, at the company’s press

conference. His answer was: “We survived. It has been a rough

market but we finished on a strong note and are stronger than we

were a year ago.”

Relatively few companies had major news announcements to

make. As often, the big news happened off-stage, with Merck &

Co. announcing that it intends to make some 15,000 job cuts by

2012, following the conclusion of its merger with Schering-Plough.

Full details were not given, but it is clear that both manufacturing

and R&D will be hit.

This was not entirely unexpected - Pfizer, GSK and

AstraZeneca had all announced similar moves last month, with the

R&D function always in the firing line. Still, it did highlight the fact

that the coming years will radically reshape the pharmaceuticals

industry and that those who serve it will have to reshape them-

selves in order to compete.

(Incidentally, the herd instinct of Big Pharma might be funny if

we weren’t talking about thousands of able, professional people

being thrown on the scrap heap to please the testosterone-fuelled

young men in the financial markets who can’t see beyond the

next quarter and whose irresponsible behaviour got us into this

mess in the first place. Oops, there I go again...).

As Cottier explained, various drivers - the patent cliff, declining

innovation rates and rising development costs, scandals in health-

care and the consequent loss of public trust, the need to focus on

drug development - ultimately mean one thing for Big Pharma.

“Go-it-alone strategies will not work; industry leaders must work

together to navigate the changing environment. Networks will be

increasingly important,” he said.

The announcements and comments made at Informex, which

are described in more detail in the news pages, reflect this. Broadly

speaking, there were two important trends: forging links to other

companies in order to gain access to enabling technologies and

acquiring or otherwise obtaining access to capacities and/or capa-

bilities in all three major regions of the world.

Thus, AMRI plugged a gap in Europe by acquiring Excelsyn. As

company executive Steve Jennings said, having a presence on the

ground is an important competitive factor in a regional market.

This was echoed by David DeCuir of Albemarle, which is expand-

ing its kilo lab of Belgium, as well as concluding an alliance with

PharmaCore.

From the other side of the Atlantic, Aesica, which manages

three ex-Big Pharma sites in the UK, now plans to acquire in the

US. Commercial director Adam Sims said that this is vital to

improving its competitiveness in the US market. Well, they will

have plenty of sites to choose from in due course...

In technology terms, both Dishman and Ampac Fine Chemicals

(AFC) have secured access to Codexis’s biocatalysis technology,

while the Almac Group launched its Rapidd service for the first

time in North America at the show. The latter is simultaneously

building up its new North American headquarters and adding

many new capabilities.

SAFC itself had no news as such, but it has invested $90 mil-

lion in the past two years in what it styles “expanding ‘technology

solutions’ throughout the drug development cycle”. A high poten-

cy API site in Madison, Wisconsin, a high potency fermentation

facility in Jerusalem and niche viral biological capabilities at

Carlsbad, California, have all been among the investments, while

many new technologies have been added.

The list goes on, with Merck KGaA’s subsequent acquisition of

Millipore being the biggest of all, but the theme is clear enough:

differentiation. Resilient though they have been down the years,

there is not much of a future for bog-standard contract manufac-

turers of fine chemicals. Those who thrive in challenging times will

have a genuine global presence and a diverse array of capabilities

that they can access, whether or not they own them. A real dedi-

cation to customer service goes without saying.

One further certainty is that many Big Pharma sites will soon be

offered for sale - some were being touted on the show floor in San

Francisco. These are usually very well-equipped, if not very flexi-

ble, and they will often come at knock-down prices, with attractive

short-term supply contracts.

Many API and fine chemicals producers, including some of the

privately-owned firms that owe their success to their company cul-

ture, such as Minakem and Hovione, have already been tempted

into acquiring sites like these. Retaining that culture while acquir-

ing the necessary global scale and differentiation may ultimately

be the most difficult challenge of all.

Dr Andrew Warmington Editor - Speciality Chemicals Magazine

Editor’s letter

Making a differencePartnership plus local bases may be the way forward in pharmaceutical outsourcing

“The generalfeeling wasconsiderablybetter than in2009. It couldhardly have beenworse.”


4 March 2010 Speciality Chemicals Magazine

Editors_letter.qxp 10/3/10 09:48 Page 4

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News



US-UK

The biggest breaking news story atInformex USA 2010 was that AMRI isto acquire Excelsyn MolecularDevelopment of the UK for €19 millionin cash. This deal will expand AMRI’sgeographic footprint, market share andcustomer base in Europe. It will costnearly €1 million to implement but isexpected to be accretive to EBITDA thisyear.

Excelsyn has 60 employees at its sitein Holywell, North Wales, which for-merly belonged to Great Lakes, andhad sales of €11 million in 2009. It pro-vides pre-clinical and Phase I-III prod-uct development and commercial man-ufacturing services to the pharmaceuti-cals and biotechnology industriesworldwide.

The company was founded by itsCEO, serial entrepreneur Ian Shott,with a USP of combining manufactur-ing, engineering and consultancy serv-ices. As Shott later admitted, this didnot really work out and the engineeringside, in North-East England, has sincebeen closed down. However, Holywellhas performed exceptionally well inrecent years.

Speaking at Informex, Steve Jenningsof AMRI said that the deal had been inthe making for some time. “We carriedout an awareness campaign in Europelast year and found that our name wasnot very well known,” he explained.“Without small-scale chemical develop-ment and API manufacturing assets inEurope we were at a disadvantage.”

AMRI had previously built up itsmedicinal chemistry capabilities inEurope via the former ComGenex inHungary. It also has laboratories inSingapore, a laboratory and chemicaldevelopment site in Hyderabad, India,and manufacturing at another Indiansite in Aurangabad, to complement itsUS manufacturing base. Chemicaldevelopment in Europe was an obviousmissing link.

“The company cultures and valuesare very similar - I have never seentwo companies line up so well and wealso hit it off personally,” saidJennings. “We have very little overlapin our customer base and what thereis is complementary. Excelsysn hasalso done a good job of running lean;their cost structure can help us too.There are a lot of synergies.”

In addition, Jennings remarked, theacquisition would help to realign the

AMRI acquires Excelsyn in €14 million deal

AMRI customer base. Excelsyn is moreslanted towards Big Pharma, whereAMRI had been affected by weakeningdemand from Emerging Pharma com-panies, and it also supplies into othermarkets new to AMRI, such as cosmet-ics, flavours and fragrances. The com-bined firm will be able to supply all ofthese at any scale.

Shott himself said that the two firmshad a “good strategic fit”, WesternEurope having been “the obvious gap-ing hole” in AMRI’s footprint. Excelsyn,he added, is at a pivotal point in thedevelopment cycle and could feed proj-ects into the Indian facilities, while alsohelping to bridge the time zone gapbetween the US and India.

Although Excelsyn had quadrupledits sales in the past five years, it was stillunable to exploit all of its customerrelationships fully because of its sizeand Shott had become convinced thatit needed to be part of a larger organi-sation. He had looked to the privateequity sector to fund a possible buy-and-build strategy but the financial cri-sis had made partners hard to find,until AMRI came along.

“The Holywell site could double itsturnover,” added Shott. “It isn’t runninghalf-empty - last year’s sales were thehighest ever, in fact - but it could oper-ate much more effectively with a mod-est investment in more equipment.”

Currently most of the reactors are inthe 500-2,000 litres range, though theygo up to 4,000. Mainly it supplies thegrams to hundreds of kilos range, car-rying out multi-step syntheses to GMPfrom labs and kilo labs, transitioning topilot plant and niche-scale productionplant assets.

“Production in Wales is not cheap,but it’s cheaper than the US and we aretold that we are not undercut on price

by Asian firms,” Shott concluded. “Ourspecialisation, though, is being fast. Wecan go from a drawing of a molecule tofirst customer deliveries in threemonths.”

Shott will remain in a consulting rolefor a further 18 months and will con-tinue to assist with customer relation-ships at Holywell. Thereafter, the sitewill be managed by Dr David Rowles asgeneral manager, reporting to Dr SteveHagen, AMRI’s vice-president of phar-maceutical development and manufac-turing. Rowles has been chief operatingofficer at the site since 2004.

Separately, the local press in AMRI’shome town of Albany, New York state,has reported that the company is suingconsultant George C. Schloemer for

some €4 million for selling proprietaryinformation to a competitor. Thismoved into the local US District Courtin February and more should followthis month.

The suit states that Connecticut-based biotech PGx Health hiredSchloemer to assist in the developmentof the API in its development drugVilazodone, when he was already work-ing for ScinoPharm Taiwan. AMRI hadpreviously won the contract for devel-opment work and believed it was set tobecome the long-term commercial sup-plier but lost out to ScinoPharm.

AMRI claims that Schloemer visitedits facilities in Rensselaer and Syracuseand that it shared detailed IP and pro-prietary information with him, notknowing then of his affiliation toScinoPharm. Following this, it says, hetold PGx that AMRI’s testing was “basi-cally a failure” and a “disaster” and gaveconfidential information to Scino-Pharm.

PGx ultimately broke its contractwith AMRI in February 2009, whichAMRI blames on Schloemer. However,PGx has separately sued AMRI inMassachusetts, accusing it of breach ofcontract in failing to produce or deliverchemical compounds as required andthus forcing it to look elsewhere, whichAMRI said was due to PGx’s failure topay promptly. Neither side has com-mented further as yet.

Excelsyn plugs a gap in AMRI’s capabilities

BASF’s Pharma Ingredients &Services business unit, which makesAPIs and excipients and carries outexclusive pharmaceutical synthesis atthe former Orgamol site in Evionnaz,Switzerland, has begun a co-opera-tion with GEA Niro. This will enable itto carry out cGMP spray drying testsand pilot productions of APIs at GEANiro’s Pharma Test Station inCopenhagen.

BASF already has “substantialknow-how” in this field, according toDr Folker Ruchatz, director of globalbusiness management for customsynthesis. However, access to theCopenhagen site, which is one of themost advanced of its kind worldwide,will give it access to cGMP spray dry-ing of APIs and formulations and thehelp of a technology leader in thefield.

Spray drying is used to improvethe bioavailability of poorly soluble

APIs. It can also be used to obtaincontrolled release, taste masking, orfine powders for inhalation or otherapplications. GEA Niro is a majorplayer in for the pharmaceuticalsindustry, offering R&D- and industri-al-scale spray dryers to process APIsand excipients and for agglomeration,encapsulation, spray congealing anddrying of final drug formulations.

News.qxp 10/3/10 09:48 Page 6

News



FRANCE-GERMANY

Groupe SNPE, France’s state-ownedproducer of space and military propel-lants and explosives, has completed thesale of its fine chemicals business unitIsochem to the German investmentfund Aurelius, subject to approval bythe French government and theantitrust authorities.

This announcement had been on thecards since December, when the Frenchnewspaper Les Echos first reported onit. Although the price was not officiallydisclosed, it has been widely reportedthat it was a token €8 million and thatSNPE will also write off debts of €50million from Isochem.

Isochem had sales of €113 millionlast year, employing 530 at four sites inFrance and another in Hungary, andmade an unspecified loss. These figureswere down from about €160 million insales and about 700 employees in2008, according to unofficial estimates.The company is also represented in theUS, the UK and Germany.

SNPE CEO Antoine Gendrydescribed Aurelius as “a strong and seri-ous partner for the successful future ofIsochem”. However, the unions werestrongly opposed to the sale and arecontinuing to fight against it.

According to Les Echos, less than twoweeks before the deal was concludedsome were trying to arrange talks withSweden’s Perstorp, which showed nointerest, while others were asking

President Nicolas Sarkozy and some ofhis senior ministers to intervene.Threats of strikes are still in the air.

Negotiations between SNPE andAurelius began in mid-December, withan exclusivity period running to theend of January. Some believe thatAurelius’s willingness to take on thewhole of Isochem counted in its favouragainst rival bids from Minakem,Axyntis, Orrion Chemicals and theInternational Chemical InvestorsGroup (ICIG), which owns WeylChem,Miteni, PPC, Corden PharmaChemand other European fine chemicalsinterests.

SNPE, which is in the process ofbeing privatised and broken up, formal-ly launched the sale of Isochem on 30June, envisaging a sale process lastingsix to eight months. It is also sellingSME, its core propellants business, toSafran and its nitrocellulose operation

in the US, Bergerac, to Dow WolffCellulosics. The former deal is beingheld up by environmental issues.

Munich-based Aurelius says that itspecialises in buying up unwantedcompanies below book value and turn-ing them around, including spin-offsfrom large corporation and medium-sized enterprises with unresolved suc-cession, liquidity and/or operationalproblems. This brings its portfolio to15, though Isochem is its first buy inchemicals.

Aurelius said that it will “support itsnew portfolio company particularlywith regard to considerable opportuni-ties for growth, such as entering newmarkets and developing new products,technologies and customer-specificsolutions”. It also plans to “intensify theinternational distribution especially inthe US and in Eastern Europe and toimprove all operational processes”

Aurelius gets Isochem from SNPE In BriefWacker name changeWacker’s Wacker Fine Chemicalsdivision is to be renamed WackerBiosolutions, following a recentrestructuring. The division will con-tinue to seek synergies betweenfine chemical and biotechnologyapproaches for the food additives,pharmaceuticals and agrochemicalssectors, the company said.However, in recent years it hasenjoyed double-digit annualgrowth from cyclodextrins and fer-mentation-generated cysteine,whereas fine chemicals have stalled.

A small reactionLonza has granted BayerTechnology Services subsidiaryEhrfeld Mikrotechnik (EMB) alicence for its process developmentand manufacturing microreactors,thereby making EMB the exclusiveworldwide manufacturer, vendorand distributor for both of them.They will also co-operate on furtherdevelopment. Lonza has won sever-al prizes for its work in the field,notably the recent Sandmeyer prizefor industrial chemistry inSwitzerland.

Chemtura grows againChemtura is to increase its capacityfor antioxidants and UV stabilisers.It will expand production of alkylat-ed phenol, the key raw material forAlkanox 240 phosphite antioxidantpowders and speciality alkylatedphenols at Catenoy, France, andproduce the newer Weston 705family of phosphite liquid antioxi-dants at multiple sites, whileTaiwan’s Everspring is to custommanufacture phenolic antioxidants,including Anox 20 and Anox PP18,based on Chemtura’s proprietaryNo Dust Blend technology.

Saudi plant is readyHuntsman and Zamil GroupHolding Company have unveiledtheir new 50-50 joint venture plantin Jubail, Saudi Arabia. The 27,000tonne/year plant will make allforms of ethyleneamines usingHuntsman technology andHuntsman will have exclusive sales,marketing and technical servicerights to its output. The two firmsare also looking into building a newmorpholine and DiglycolamineAgent amines plant in Jubail.

Isochem runs a network of sites in France

GERMANY-US

Merck KGaA has agreed to buy USfirm Millipore for €5.3 billion in acash and loan deal, creating a €2.1billion/year life sciences player. Bothboards have agreed and the mergershould clear in 2H 2010, subject toshareholder and regulatoryapproval.

Millipore, which employs 6,000worldwide and turned over €1,250 bil-lion last year, offers various products,technologies and services used bypharmaceuticals and biotechnologycompanies and academia in laboratoryand manufacturing processes. This isalso an important area for Merck’sChemicals business, which will risefrom 25% of group sales to about 35%as a result.

Dr Karl-Ludwig Kley, chairman of theexecutive board of Merck, said that thiswas “a combination with an excellentstrategic fit, which will allow us to coverthe entire value chain, offering integrat-ed solutions beyond chemicals. Bycombining Millipore’s bioscience andbioprocess knowledge with our ownexpertise in serving pharma customers,we will be able to unlock value in ourchemicals business and transform it

into a strong growth driver for Merck,”he added.

The Millipore headquarters atBillerica, Massachsetts, will be retainedand combined with Merck’s own USchemicals headquarters, as will the sen-ior management and the Milliporebrand. There is no word yet as towhether any job cuts or any rationalisa-tion of the manufacturing base or prod-uct range are planned, though Mercksaid that it expects to achieve about€75 million in synergies within threeyears of closing.

The announcement came shortlyafter Millipore said that it was conduct-ing a strategic review, in which a salewas one option. It was rumoured thatinstrumentation giant Thermo Fisherhad made a €4.4 billion offer, whichMerck comprehensively trumped.

Merck KGaA buys up Millipore

Kley - Millipore can add value

News.qxp 10/3/10 09:48 Page 7

EUROPEAN UNION

Some of Europe’s leading fine andspeciality chemicals companies,including Arkema, Umicore, MerckKGaA and Novozymes, are amongthe 28 partners taking part in theEuropean Multilevel IntegratedBiorefinery Design for SustainableBiomass Processing, or EuroBioRef,project. This was formally launchedon 1 March.

Co-ordinated by Professor FranckDumeignil of the Centre Nationalede la Recherche Scientifique (CNRS)in France, the project has beengranted €23 million in funding fromthe EU’s 7th Framework Programme.EuroBioRef, CNRS said “will dealwith the entire process of transfor-mation of biomass, from fields tofinal commercial products.”

EuroBioRef aims to develop ahighly integrated and diversifiedbiorefinery concept, including multi-ple non-edible feedstocks and multi-ple processes - chemical, biochemi-cal and thermochemical alike - toproduce both chemicals and aviationfuels. It will also seek to facilitatebetter co-operation among actors toimprove the efficiency of the processand overcome the fragmentation ofthe biomass industry.

“This programme is an excellentopportunity to fill the gap betweenagriculture and the chemicals indus-try,” said Dumeignil. “It integratesthe whole biomass chain into a com-

mercial, viable and adaptableapproach, allowing a sustainablebio-economy in Europe.”

Specific targets include improvingcost-efficiency by 30% by means ofbetter reaction and separation effec-tiveness, reduced capital invest-ments, improved plant and feed-stock flexibility, plus shorter produc-tion time and logistics. Energy useshould also be cut by 30% and feed-stock consumption by 10%, whilezero waste should be generated.

Only Umicore has publicly com-mented on its role, which will be todevelop and make new ruthenium-based catalysts for the chemicaltransformation of feedstocks. Thecompany’s Precious MetalsChemistry business unit has accessto metathesis technology and otherareas of catalysis, based on its back-integration into primary metals.

Also taking part are various tech-nology-based companies, universi-ties and research institutes in France,Germany, Belgium, Norway,Denmark, Greece, Switzerland,Portugal, Italy, Poland, Sweden, theUK and Bulgaria, plus SociétéAgricole de Befandriana-Sud &Partners in Madagascar.

In related news, BASF has justbroken ground for a new plant atGuaratinguetá in Brazil. This willhave 60,000 tonnes/year capacityand will supply sodium methylate intandem with the main Ludwigshafenfacility for use as a catalyst in theproduction of biodiesel. The firmdescribed sodium methylate as “anefficient and reliable catalyst” in thisapplication.

Meanwhile, however, US-basedion exchange firm Purolite andIsraeli biocatalysis specialistTransBiodiesel will work on enzyme-loaded ion exchange resins toreplace traditional trans-esterifica-tion processes based on a new,patent-pending process. The compa-nies claim that their enzyme-loadedion exchange resin replaces sodiummethylate and can simultaneouslyesterify free fatty acid and trans-esterify fats and oils, eliminatingsome of the downstream issuesbiodiesel producers typically face.

Another firm active in the fieldwith a new announcement isRockwood subsidiary Sachtleben. Ithas developed catalytically activeparticles using a fluid bed systemthat is about to be introduced atcommercial scale at the facility of itsbiodiesel-producing partner, EverCat Fuels, in Minnesota. Thisprocess, the two claim, could “revo-lutionise the production of biofuelsusing sustainable and environmen-tally friendly means”.

EuroBioRef project to buildbiorefinery of the future

News



In BriefPPD opens Irish facilityGlobal CRO PPD has officiallyopened its €14 million contractresearch facility in Athlone, Ireland,with financial support from theIrish Development Agency. It hasalready hired 21 staff and expectsto employ 250 people there intime. The facility includes a 1,670m2 analytical testing laboratory fortests at all stages of clinical pro-grammes and marketed products,plus a clinical supplies operation,regulatory services, product licens-ing and marketed product support.

Dottikon cuts hoursDottikon Exclusive Synthesis, aSwiss fine chemicals and APIs firmspecialising in hazardous chemistry,announced in mid-February that itintends to introduce short hours insome sections of its plant fromMarch and would be submittingapplications accordingly. This isbeing done “to absorb short-termfluctuations in capacity utilisation”.The company expects its full-yearresult for 2009-10 to be lower thanthose of the previous year.

RD&T times threeSolvay is to create a cluster of threeresearch, development and technol-ogy (RD&T) centres in Asia by theend of 2011. One in Vadodara inIndia’s Gujarat state will focus onhigh-performance polymers, organ-ic chemistry, nanocomposites,biotechnology and green chem-istry. Another in Ulsan, Korea, willwork mainly on electronics, lithiumion batteries, photovoltaic cells andother high-growth market, while athird in the Shanghai area will coverall bases, with no defined speciali-sation.

CORRECTIONIn the January 2010 edition, thename of the author of AMRI’s arti-cle ‘Fragment Screening inBiological Arrays’ (pages 24-25)was mis-spelled in the standfirstand again in the contact details. Thecorrect name is Dr Gergely Makaraand his email address [email protected]. In addition, certain structureswere not reproduced on the pagebecause of technical problems.Please contact us for a correctedPDF of the article.

GERMANY-UK

Evonik Industries, which recentlyacquired API manufacturing facili-ties in the US for the first time viathe former Eli Lilly facility inTippecanoe, has made two smaller,technology-based acquistions inEurope. Shortly after buying the cat-alysts business of H.C. Starck inGermany, it also bought MembraneExtraction Technology (MET) in theUK. Terms were not disclosed ineither case.

The former deal brings Evonik theAmperkat range of activated nickel

and other metal, or ‘skeletal’, cata-lysts and customised supported cata-lysts, which are widely used in theproduction of APIs, sweeteners andstarting materials for polyurethanes.After a short transition phase, it willrelocate production from Starck’sGoslar site to its own at Hanau.

The company commented that itscurrent and newly acquired productgroups “are used in similar marketsegments, but their activity andselectivity differ enormously”, sothis expands its capablities. In partic-ular, it enables Evonik to make acti-vated metal catalysts based on spray

alloys and in tablet form, giving itadditional freedom when designinghigh-performance catalysts.

With London-based MET, mean-while, Evonik is adding new capabilitiesto its P84 fibres and high-performancepolymers business and will become amajor player in organic solvent nanofil-tration. Membrane-based technologiesare expected to see strong growthbecause of their energy-efficiency andlow environmental impact; MET’s issaid to be used in a wide range ofchemical processes, including finechemicals, simplifying product purifi-cation and saving energy.

Evonik buys two more operations

News.qxp 10/3/10 09:48 Page 8

News



US-UK

Almac Sciences of the UK usedInformex USA 2010 to launch itsRapidd service, which aims to shrinkthe early stage drug developmentcycle radically, as well as to showcasesome newly arrived differentiatingcapabilities and the progress of itsnew North American headquarters.

Rapidd was originally launched inEurope at CPhI Worldwide lastautumn (see SCM, October 2009).According to Denis Geffroy, vice-pres-ident of business development, itlooks “extremely promising - we havetwo ongoing projects and a nicepipeline”. Both projects, coincidental-ly, are for the GMP production ofpeptides. In one case, nearly 12months were shaved off the timeline,though Almac would not claim thatas typical.

At the original launch, Almac hadnamed Covance as one of its CROpartners in Rapidd and it revealed atInformex that CIT, a Paris-based firm,is another. A third will be namedsoon. This should be the last, as partof the appeal is to simplify the oftencomplex clusters of firms and capabil-ities involved in early stage projects.

Another new capability in productdevelopment is an Xceldose 6005precision powder micro-dosing sys-tem that Almac has just validated.This, said Geffroy, can help decreaseprocessing time and API consump-tion, thus leading to “significant” sav-ings in cost, time and material as APIsbecome ever more complex.

The new North American head-quarters in the northern part of

Philadelphia is also progressing andshould, Geffroy said, be completed bythe end of the year at a cost of around€90 million. This will bring the totalnumber of employees to over 3,000 -almost four times the number whenhe arrived at Almac in 2004.

The new facility will have “a lot ofdifferentiating capabilities”, Geffroynoted. These will include both analyt-ical services (API and drug productdevelopment, method developmentand validation, stability studies, etc.)and solid state services (physical formscreening, crystal engineering, APIand dosage product characterisation,etc.).

Subsequently, Almac ClinicalServices, another division of theAlmac Group, launched its web-basedShipping Temperature ElectronicMonitoring System (STEMS). This isclaimed to be unique in the pharma-ceuticals and biotechnology sector,offering complete, instant tempera-ture reporting at all stages in the clin-ical supply chain and thus enablingusers to make instant decisions with-out having to monitor returns or faxresults.

Finally, Almac has expanded itsradiolabelling capabilities to include14C API and InvestigationalMedicinal Product (IMP) supply. Thenew laboratories, officially opened atthe main Craigavon facility inNorthern Ireland on 26 February, willinclude 14 work stations for synthe-sis and six others, each staffed by adedicated radiochemist. They alsoinclude a dedicated finishing suitefor IMPs for use in clinical trials andthe last steps in API manufacture.

Almac adds to NorthAmerican capabilities

FRANCE

Groupe Novasep and its customerProvepharm of Marseille, which devel-ops and markets drugs patented by itsparent, the Provence TechnologiesGroup, have successfully validated thecGMP manufacturing process forProvepharm’s Proveblue API. The twodescribed this as “a major step inbringing compliant methylene-blue-based drugs to market”.

Proveblue is the first methyleneblue-based API. It is also the firstgrade of methylene blue to complywith European Pharmacopoeia andICH requirements and the EuropeanMedicines Agency Guideline on thespecification limits for residues ofmetal catalysts.

Hitherto, methylene blue has beenused mainly as a dye in therapeuticand diagnostic applications and as anantidote to blood poisoning, but itexisted only in highly impure form,with excessive levels of heavy metals.As Novasep marketing director JeanBléhaut told SCM at Informex USA2010 in San Francisco, it is a strongchelatant that is hard to manipulate.The regulatory agencies were there-fore keen to have a company come upwith a purer product.

Novasep scaled up Provepharm’soriginal synthesis process, includingthe development and transfer of com-plex analytical methods, within theexisting equipment at the formerFinorga site at Chasse-sur-Rhône nearLyon, from February 2009. This wasvalidated in September and a success-

ful French Medicines Agency followedin October. The process can reducemetal impurities by up to 99% andcan yield “significantly improved”organic purity, it is claimed.

“This was a very typical project forNovasep and a very nice example ofworking with the chemistry a cus-tomer had developed,” said Bléhaut.“The customer came to us in direstraits, because they needed to findsomeone to scale the chemistry up.”

Simultaneously, the EMEA hasaccepted for rapid evaluation theMarketing Authorisation Applicationfor the methylthioninium chlorideProveblue solution for injection underthe EU centralised procedure. This, ifsuccessful, could lead to a singleauthorisation in all 27 EU membercountries.

The move also opens the way forR&D into more methylene-blue-based drug products in therapies suchas urinary and ocular antiseptics, anti-malarial agents and treatments forneurodegenerative diseases, amongothers. Provepharm is now in discus-sion with the US regulatory agencies.

Proveblue has beenproven by Novasep

Bléhaut - Good example of workingwith customer chemistry

News.qxp 10/3/10 09:48 Page 9

News



US

Albemarle has reached a new partner-ship with PharmaCore, a US-basedsupplier of custom organic synthesisservices for pharmaceutical interme-diates and APIs. Under this, cus-tomers will be able to transfer long-term projects requiring higher capaci-ty than PharmaCore can offer toAlbemarle Fine Chemistry Services’(FCS) sites in South Haven, Michigan,Tyrone, Pennsylvania, and Orange-burg, South Carolina.

Speaking at Informex USA 2010,David DeCuir, director of AlbemarleFCS, stressed that this is an informalagreement. It does not involve anyinvestment or tie-in beyond technolo-gy transfer from PharmaCore’s cGMPpilot plant in High Point, NorthCarolina, which was itself expandedlast year.

“We’ll have to earn the projects,but we are confident that we will earnquite a few,” DeCuir said. Thearrangement began with anAlbemarle customer recommendingPharmaCore as a supplier of small-scale synthesis services. The two com-panies then began talking with eachother. Albemarle hopes to developsimilar relationships with other small-scale firms.

Albemarle FCS, which offers prod-ucts, custom manufacturing andprocess scale-up services to indus-tries including pharmaceuticals, cropprotection and other speciality mar-kets, is the smallest of Albemarle’sthree divisions, the others beingPolymer Solutions and Catalysts. In2009, it turned over about €185 mil-lion of the €1.5 billion total, manag-ing to grow despite the economicdownturn.

The division expects to grow by upto 30% in 2010, according to DeCuir,based on “a significant improvement

in business relations with customers”.Three new people should be taken on- two in sales, one in business devel-opment - and construction has begunof a kilo lab at the company site inBelgium, with a validation campaignfor Siga already booked in.

The kilo lab will develop individualprojects for transfer to the US sites,not unlike PharmaCore. “This is anattempt to develop both relationshipsand chemistry a bit more fully beforetransferring to the US. We find thatworking locally with people worksbest,” DeCuir remarked.

Albemarle does not have large-scalecontract manufacturing capacity inEurope, though this may change. Thecompany plans to spend hundreds ofmillions of dollars on acquisitions thisyear, possibly on small bolt-on acquisi-tions in the €35 million range, but it ismore likely to look at substantial buysof around €75-150 million.

“We are not discarding the firstoption but we are really lookingmainly at the second,” DeCuir said.“It could be companies serving phar-maceuticals, agrochemicals or othermarkets, because we cast a wide net.”

Albemarle partners with PharmaCore

PharmaCore will funnel early projects from its facility (left) through to Albemarle’s (right)

US-INDIA

Biocatalysis specialist Codexis usedInformex USA 2010 to announce sep-arate collaborations in pharmaceuticalmanufacturing with DishmanPharmaceuticals & Chemicals of Indiaand US firm Ampac Fine Chemicals(AFC). The latter has also recently con-cluded an agency agreement in Japanwith Inabata & Co.

Under these deals, Codexis’s propri-etary biocatalyst technology will beused in unspecified therapeutic prod-ucts in the two firms’ portfolios, with aview to cutting costs and increasingmanufacturing efficiency. Environ-mental benefits are also claimed.Codexis is currently seeking an IPOafter having to abandon one in theweak financial markets of 2009.

The agreement with Dishman willinvolve working exclusively to supplyintermediates and APIs made using

Codexis technology to “a select groupof innovators”. Dishman, which oper-ates 12 facilities in India, China,Switzerland and the UK, will also beCodexis’s preferred CMO partner withother innovators.

“This gives us a technology differen-tiator, of which we don’t have many atpresent, with all the advantages bio-catalysis brings. Codexis get the bene-fit of selling their technology to ourcustomers,” Rhona Cameron, commer-cial director of Dishman subsidiaryCarbogen Amcis, told SCM at theshow. Although the deal had just beensigned, she added, it is already gener-ating a lot of interest and a number ofprojects are under evaluation.

In January, Carbogen Amcisopened its new high potency facilityat the Dishman headquarters inAhmedabad, the first of its kind inIndia. The next milestone forDishman will be the opening of a

GMP API facility at the ShanghaiBusiness Park, giving the company asecond source of supply for large-vol-ume projects in the Asian market.

This latter project has been slightlydelayed but, according to Vyas, shouldbe in operation in about August-September. The facility, in whichDishman has invested about €7.4 mil-lion will cover some 40,000 m2 andwill make both intermediates and qua-ternary salts for the global pharmaceu-ticals market.

Despite some reports to the con-trary, Cameron said, Carbogen Amcishas not closed any facilities. Due to thedifficult market in early phase develop-ment, there has been some reorganisa-tion at the main Bubendorf site inSwitzerland and whenever jobs are cutthere, it has to be notified to the gov-ernment and becomes a matter of pub-lic record. However, there have beenand will be no actual closures.

Fewer details were given aboutCodexis’s deal with AFC, which isbased in Rancho Cordova,California, and custom manufac-tures pharmaceutical fine chemi-cals, including high potency APIs,but it is understood to refer to highenergy chemistry applications. Thisis one of AFC’s key specialities,alongside industrial-scale SMB chro-matography.

The other deal, making InabataAFC’s exclusive agent in Japan, isdesigned to give the companyaccess to the Japanese market for itsAPI manufacturing technologies.Company president Aslam Maliksaid that Inabata has “a strong trackrecord of successfully pairing tech-nologies with client needs andknows the Japanese marketplacewell”, enabling it to find partnerswho could benefit from using AFCtechnologies.

Codexis to work with Dishman and Ampac Fine Chemicals

News.qxp 10/3/10 09:48 Page 10

News



GERMANY-INDIA

Kiri Dyes & Chemicals (KDCL) of Indiahas announced that DyStar’s shutteredoperations in Germany are ready toresume. The firm has secured financingfor the acquisition of DyStar fromPlatinum Equity and met other condi-tions, including anti-trust approval fromGermany’s Federal Cartel Office, thuscompleting the deal.

This means that about 750 jobs inGermany, slightly more than half ofthe 2009 total of about 1,300, havebeen secured. Plans to resume pro-duction as quickly as possible withinQ1 at four of the sites run by DyStarTextilfarben GmbH & Co. Deutsch-land KG. The DyStar Group Holdingcompany will be located inSingapore.

“From where we stand, this is amajor success to be able to save fourproduction sites in Germany with somany jobs, given the current difficulteconomic setting,” said the insolvencyadministrators, Miguel Grosser of JafféRechtsanwälte and Dr StephanLaubereau of Pluta Rechtsanwalts.

The arrangement will secure 90 jobsat the indigo facility in Ludwigshafen,which was the only one to carry on fulloperations while DyStar was in admin-istration, plus about 236 in Leverkusen,130 in Brunsbüttel and 260 inFrankfurt. The latter three had startedto lay employees off from Novemberfor lack of funds to continue payingsalaries.

In addition, the jobs of 50 morepeople who carry out central functionsin Frankfurt from purchasing to saleswithin the separate subsidiary, DyStarTextilfarben GmbH, have been saved.These employees had carried on work-

ing even after insolvency proceedingsbegan on 1 December.

KDCL stated that “the vast majorityof the staff laid off in total can now bere-employed”. The largest DyStar facili-ty at Geretsried, however, is not beingpurchased or resuming production.Indications are that KDCL is still seek-ing to sell it.

DyStar and KDCL will operate asindependent companies and DyStarsaid that it will “continue to offer itscomprehensive range of dyes, processand effect chemicals as well as servicesto the textile industry”. It will alsomaintain leather industry activities viathe Boehme brand.

Production of some Boehme chemi-cals, including Cutapol and Eskatan,will transfer from Geretsried to othersites, while the Solvaderm range of dyeswill also continue. According to DyStarthere are “significant opportunities bycombining its own forward integrationto the leather industry with KDCL’sbackwards integration into raw materi-als and intermediates”.

DyStar, which united the textile dyesand colours interests of BASF, Bayer

and Höchst in 1995, originally filed forinsolvency last September, threateningall bar about 160 of the employees withredundancy.

The administrators reported that twoother firms were also interested butonly KDCL’s offer met the requirementsand the necessary financing conditions.This will catapult the Ahmedabad-basedfirm into the top rank in dyes, a marketin which DyStar was a global leaderwith a 21% market share and sales of€830 million in 2008.

Manish Kiri, who is already manag-ing director of KDCL, has been namedthe new chairman of DyStar. Dystar’sformer vice president for strategicmarketing Steve Barron becomesCEO, while former CEO J. Mark Allan,will remain with the company as astrategic adviser for six months tohelp in the transition of duties andresponsibilities.

Other appointments includeHarry Dobrowolski as COO and BartVan Kuijk, previously sales area man-ager for South Asia, as chief market-ing officer. Viktor Leendertz remainsas CFO.

DyStar operations set to restart

DyStar’s Frankfurt head office continued working throughout insolvency

JAPAN

Fujifilm has announced the establish-ment of its majority-owned sub-sidiary Fujifilm Pharma (FFP) in theJapanese pharmaceuticals market.Plans are for the firm, which was for-mally established in November 2009,to begin operations in April by mar-keting generic drugs.

Mitsubishi, which is to hold 15% ofFFP, has been appointed to helpsource APIs and pharmaceuticalproducts from within and outsideJapan, and develop overseas saleschannels. Another minority owner,drug wholesaler Toho HD (5%), willtake care of marketing and logisticsto institutions and sales to both insti-tutions and pharmacies.

FFP will work with Fujifilm’s DrugDiscovery Research Laboratories affili-ate, which was established last sum-mer, in using the proprietary FTD‘technology*2’. This is said to improvepharmaceutical solubility, enhancechemical stability, add a sustainedrelease property and expand the avail-ability of dosage forms. The hope isthat this will enable the firm to develophigh-added value generics and evolveinto an innovator in its own right.

Some technologies developed forphotographic chemicals are expectedto find applications for FFP, notablyemulsification, dispersion, nanoparti-cles, nanocapsule formation andporous and multilayer thin films forchemical formulation and targeteddelivery. Fujifilm is also active in phar-ma via its fine chemicals arm, FujifilmFine Chemicals, the Toyama Groupand radiopharmaceuticals firmFujifilm RI Pharma.

Fujifilm to enterpharma market

News.qxp 10/3/10 09:48 Page 11


Catalysts


Organozinc halides in catalysisDr Andreas Leitner of BASF looks at the use of organozinc halides as stable functionalised nucleophiles for cross-coupling reactions

Organozinc reagents have emerged as powerful nucle-ophiles in organic synthesis.1 The covalent nature ofthe carbon-metal bond of organozinc halides entails areduced reactivity but gives these organometallics a uniquecompatibility to sensitive functional groups (Figure1).2 In con-trast, Grignard reagents and organolithium compounds have acarbon-metal bond with an ionic character, which is responsiblefor the higher reactivity to electrophiles but consequently caus-es a lower functional group tolerance.

Although organozinc halide compounds were discovered atthe beginning of the 19th century, the chemical community didnot exploit the potential afforded by their reduced reactivity formany decades.3 The discovery of the transmetallation reactionof an organic moiety from zinc to transition metals, such as cop-per, palladium, nickel and even inexpensive and environmen-tally benign iron, opened new avenues for the application oforganozinc halide compounds in organic synthesis.4

In the 1970s, Negishi pioneered the development of C-Cbond forming reactions of organic halides using differentorganometallic donors with low reactivity, such as organozinchalides and palladium, as catalysts.5 The Negishi reaction hasseveral advantages. In particular for synthetic challenges, where

sensitive, unprotected functional groups are required on thenucleophile and electrophile, it often outperforms alternativetechnologies.

For instance, Lipshutz reported that the cross-coupling of 4-Cl-benzaldehyde with 4-cyanopropylzinc bromide accom-plished in a high yield of 80% in the presence of Ni-C as a cat-alyst. No side reaction by an uncatalysed attack of the organoz-inc reagent to the aldehyde was observed (Figure 2).6 The tol-erance to sensitive functional groups on both cross-couplingpartners can significantly reduce the number of protecting-group manipulation steps and consequently lead to a higheroverall yield.

Organozinc reagents have emerged as powerful nucle-ophiles to introduce a cyclopropyl or a 2-pyridyl group byNegishi cross-coupling. Both structural motifs can be found inimportant synthetic intermediates and APIs.7 Although thesereagents have been known for a long time, the high stability ofcyclopropylzinc bromide and 2-pyridylzinc bromide wasdescribed only recently.8

The stability of several organozinc compounds was investi-gated by a shelf life study at room temperature and their reac-tivity monitored by a cross-coupling reaction with 4-bromoben-zotrifluoride in the presence of 2.5 mol% Pd(PPh3)4.9 After 12months at room temperature, the organozinc halide solutionsperformed equally well in the test reaction as the freshly pre-pared reagents, and no degradation products were detected bygas chromatography.

ZnX

R1

R2R

C- M+

R1

R2R

M = Li+, MgX+

• Ionic carbon-metal bond• Very high reactivity• Low chemo selectivity• Precursor for boronic acids

• Covalent carbon-metal bond• Reduced reactivity• High chemo-selectivity• Direct use in reaction

H

O

Cl + IZn CN

5% Ni/CPPh3

THF,60˚C

H

O

CN

80%

O2N

I

+

N ZnBr

0.1 mol% Pd(PPh3)4

THF65˚C

O2N

N

conversion: 97%

turnover number: 970

EtOZnBr

O+ Br

O

OMe

2% Pd(PPh3)4

20˚C22 hours

THF

EtO

O OMe

O

77% isolated yield

Extractionwith toluene

Phaseseparation

Organic phase18,000 ppm Zn

Water phase36,000 ppm Zn

Treatment withMSA-FC Si-3

Precipitationwith NaOH

Product

Catalysts



This shelf-life study has important consequences for theapplication of organozinc reagents on scale. Since no significantdegradation at room temperature under inert atmosphereoccurs, the cyclopropyl and 2-pyridyl reagents can be safelyshipped and stored with assured quality. Currently, we are con-ducting stability studies of several organozinc reagents bearingfunctional groups to evaluate the stability of organozincreagents in more detail.

The scope of the Negishi cross-coupling of 2-pyridylzinc bro-mide and cyclopropylzinc bromide was investigated in moredetail (Table 1). In general, the selected organic halides weretransformed into the desired cross-coupling product withoutdiligent optimisation of reaction conditions, catalysts and otheradditives. Aryl bromides and iodides bearing functional groupslike an enolisable methyl ketone, ester, nitrile, aldehyde, etheror nitro group were coupled in high conversions and yields inthe presence of Pd(PPh3)4 or Peppsi.

The substitution pattern of the aryl halide had no significantimpact on the reaction rate. 2-, 3- and 4-bromo benzonitrilesefficiently coupled with comparable high reaction rates pro-

is viding the final product in up to 93% isolated yields (Entries6-9). Heterocycles like 2-bromo-thiazole were converted intothe cross-coupling product within one hour and the productwas isolated in a moderate yield of 43% (Entry 10).

Electron-neutral bromobenzene and the electron-rich 4-bromo-anisol reacted with 2-pyridylzinc bromide to thedesired cross-coupling product in 85% and 82% isolatedyields respectively (Entries 13 &12).

All of the reactions described here were conducted under aninert nitrogen atmosphere, applying bulk THF with a water con-tent of about 200 ppm. Under these conditions, turnover num-bers of up to about 1,000 were accomplished, which corre-sponds to a catalyst loading of 0.1 mol% and is in a useful rangefor application at scale (Figure 3).

The work-up of the Negishi cross-coupling was conducted byan acidic/basic quench followed by an extraction with an organ-ic solvent such as toluene. Figure 4 shows a representativecross-coupling of 4-ethoxy-4-oxobutylzinc bromide with 4-bromo-methylbenzoate in the presence of 2 mol% Pd(PPh3)4.After the quench, extraction with toluene and phase separation,

Entry Substrate RZnX Catalystb Reaction time (hours)/ Product YieldaTemperature (%)

1 X=I CprZnBr Pd(PPh3)4, 2.5% 1/65°C 99 (GC)2 X=Br CprZnBr Peppsi, 1% 1/65°C “ 753 X=Cl CprZnBr Peppsi, 1% 4/65°C “ 754 CprZnBr Peppsi, 1% 1/RT 97 (GC)

5 CprZnBr Peppsi% 4/65°C 92 (GC)

6 CprZnBr Pd(PPh3)4, 2.5% 18/65°C 99 (GC)

7 “ 2-PyZnBr Pd(PPh3)4, 2.5% 16/65°C 91

8 CprZnBr Pd(PPh3)4, 2.5% 18/65°C 91

9 CprZnBr Pd(PPh3)4, 2.5% 24/65°C 75

10 2-PyZnBr Pd(PPh3)4, 2.5% 1/65°C 43

11 2-PyZnBr Pd(PPh3)4, 2.5% 1/RT 60

12 2-PyZnBr Pd(PPh3)4, 2.5% 4/65°C 82

13 2-PyZnBr Pd(PPh3)4, 2.5% 4/65°C 85

14 2-PyZnBr Pd(PPh3)4, 2.5% 1/RT 77

Notes: a - Isolated yields unless stated otherwise. Reactions conducted in THF on 10 mmol scale, b - Catalyst loadings are not optimised. c - 2- pyridylzincbromide (2-PyZnBr) & cyclopropylzinc bromide (CprZnBr) were prepared as 1M solution in THF by BASF

X

O

Br

O

OMe

I OCH3

Br CN

CN

Br

CN

Br

N

SBr

Br

O

H

Br OCH3

Br

I NO2

CN

CN

N

NC

CN

N

S

NO

HN

OCH3N

N

N

NO2

OCH3

O

OMe

O

Table 1 - Cross-coupling reactions of cyclopropylzinc bromide & 2-pyridylzinc bromide

BASF.QXP 10/3/10 09:49 Page 13

Catalysts



a zinc metal content of 18,000 ppm was measured in theorganic product solution.

Treatment with the metal scavenger MSA-FC Si-3 removedthe zinc salt impurities to a level of 10 ppm and the final prod-uct could be isolated with 77% yield. The aqueous waste waterstream was treated with an aqueous base such as sodiumhydroxide or calcium hydroxide and residual zinc content was

Progress in gold catalysisAntony Wright of Strem Chemicals describes emerging patterns in the use of gold catalysts inorganic synthesis



Catalysts

To understand the emergingimportance of gold in catalysis,one need only consider thechemistry it promises to replace.Historically, dating from its discovery byM.G. Kucherov in 1881, the catalysts ofchoice for the hydration of alkynes toketones have been soluble Hg(II) salts.

Commercial production of acetalde-hyde from acetylene using an acidicmercury catalyst began in 1916 inGermany and in 1932 in Japan.Unfortunately, mercury wastes from theJapanese plant accumulated in fish asmethylmercury compounds, poisoningthousands of people over a 30-yearperiod around the city of Minamata.

The mercury process became obso-lete as the production of acetaldehydefrom a different feedstock, ethylene,commenced in 1960 using the Wackerprocess, with palladium as the catalyst.This did not mark the end of the C≡Cbond as a synthetic precursor, however.Over the last 20 years, chemists havedeveloped remarkable processes thatconvert complex alkynes to interestingfine chemicals based on the discoverythat Au(I), which is isoelectronic withHg(II) but lacks its toxicity, is also a pow-erful catalyst for alkyne additions.

In general, an efficient homoge-neous catalyst will, in small amounts,convert a substrate to a product selec-tively and rapidly without any concur-rent catalyst deactivation or inhibitioncaused by impurities, side reactions or

solvent. Ideally, the catalyst should betunable for particular substrates to pro-duce the desired products selectivelyand allow enantioselective reactions.

Although strong acids will hydratealkynes slowly and a wide selection ofmetal-based catalysts within PeriodicTable Groups 8 through 12 will acceler-ate hydration, almost all such catalystsdeactivate or become erratic after atime due to side reactions, for examplethe formation of catalytically inactivemetal carbonyls.1

Perhaps the most promising alterna-tive catalysts to be discovered for addi-tions to alkynes have been based onAu(I), which is isoelectronic with Hg+2.Like mercury, these catalysts act asLewis acids with regioselectivity follow-ing Markovnikov’s rule.

Whereas simple inorganic goldsalts are quickly inactivated by reduc-tion to metallic gold, there are nowseveral outstanding examples of cata-lysts that are gold complexes, perhapsthe most successful being Au+1

cations stabilised and solubilised byphosphine ligands, especially whencombined with non-nucleophilicanions (R3PAu+ X-).

Such catalysts are soft Lewis acids inPearson HSAB terminology and theyfunction very effectively on soft Lewisbases, such as alkynes. The Lewis acidcharacter of Au+ is enhanced by con-tracted gold 6s orbitals, whereasexpanded 5d orbitals are said to reduce

gold nucleophilicity, reduce the occur-rence of oxidative addition reactions ongold, make Au+ tolerant of oxygen and,in the alkyne hydration reaction, reduceback-bonding from gold to coordinatedalkyne π* anti-bonding orbitals, therebyfavouring the addition of water to morepositively charged β-carbon in the goldπ acid complex. (Figure 1, HOH =E+Nu-, 1→2).2

In 1968, Teles published the firstreports of such catalysts applied tothe addition of methanol to a widevariety of alkynes. The addition oftwo molecules of methanol occurredalmost exclusively at the more highlysubstituted carbon atom to produceacetals (Figure 1: formally 1→2→4,repeated twice).3

Typically, the best active catalystswere formed by the dealkylation of theprecursor R3PAuCH3 in situ with strongacids such as CH3SO3H to form, forexample, R3PAuOSO2CH3, which

ionises in solution to the active catalyst,R3PAu+. The presence of excess miner-al acid accelerated the rate.

The catalysts performed at extreme-ly low levels and were stable, neitherbeing reduced to the metal, nor form-ing carbonyls. Turnover frequencies ofup to 5,400 h-1 with total turnovers of105 moles were achieved. Consistentwith a Lewis acid mechanism, ratesincreased as the ligand was tuned to bemore electron-withdrawing in the seriesPh3As

Catalysts



Organic chemists have been delight-ed to find that, beyond the addition ofsimple protic molecules to acetylene,interesting complex structures areaccessible in high yield using homoge-neous gold catalysis with multifunction-al unsaturated substrates usually con-taining at least one alkyne. The mois-ture- and oxygen-tolerant chemistry isbased on cascade reactions driven bythe high energy released on addition tothe triple bond and the ability of gold tostabilise each ensuing cationic reactionintermediate.4

Typically, as shown in Figure 1, theelectrophile attacking 2 is an interme-diate cationic site, which can eitherdisplace gold from the α-carbondirectly via pathway A or transmit pos-itive charge to the α-carbon throughthe π system via pathway B. Thischarge is stabilised by the gold car-benoid character of intermediate 3.This, in turn, is explained by back-bonding from the relatively expandedfilled gold 5d orbitals into the devel-oping neighbouring carbocation.Figure 2 gives an example involvingthe participation of pathway B.

Propargylic carboxylates canundergo metal-catalysed ester migra-

tion. Gold, as AuCl3 or in situ-pre-pared Ph3PAu+ (Ph3PAuCl + AgSbF6)catalyses the reaction much fasterthan other metals can. After estermigration, a positive charge developson carbon neighbouring gold, follow-ing pathway B, the carbenoid-directedpathway. Interestingly, from a synthet-ic point of view, the carbenoid inter-mediate reacts like a real carbene,inserting in a broad range of co-mixed olefins to make cyclopropanesin 60-70% yields.5

The gold carbenoid structureappears to be planar, as expected fora carbene, since optically enrichedpropargylic carboxylate reactantsform racemic products. It was, how-ever, possible to prepare a chiralproduct using a different approach.Thus a gold catalyst using the chiralphosphine ligand R-DTBM-SegPhoswas able to achieve 94% ee.Generally, however, it has been diffi-cult to design gold catalysts that areeffective for enantioselective reac-tions, both because of the reluctanceof Au(I) to accept chelating ligandsand because the linear geometrypositions the ligand remotely relativeto the active site.

It has become possible to control thecourse of a synthesis by fine tuning theelectronic properties of R3PAu+ cata-lysts, for example by modulating theelectron-donating ability of the phos-phine ligand. One would expect that anelectron-rich ligand would stabilise agold carbenoid intermediate and sofavour any pathway involving such anintermediate.

Recently, a substrate was designedfor which both pathway A and B(Figure 1) were possible, potentiallyleading to different products. Indeed,it was found that electron-donatingligands favoured pathway B, whichinvolves a carbenoid intermediate,whereas electron-withdrawing ligandsfavoured pathway A (Figure 3).6

There are likely to be more examplesof ligand-controlled reactivity reportedin the future.

Heterogeneous catalysis The catalytic chemistry of gold catalystsprepared on solid supports, such as alu-minum oxide, titanium dioxide, ironoxide and zinc oxide, has developedquite differently than that described forhomogeneous gold. Most develop-ment efforts have focused on certainunique capabilities of such catalysts thatcannot be duplicated with cheapermetals. An extensively studied exampleis the unique ability of certain gold cat-alysts to convert CO to CO2 with oxy-gen at temperatures as low as -76°C,though our understanding of this reac-tion is as yet inconclusive.

It is known that molecular oxygenwill not adsorb under UHV conditionson pure Au(111) surfaces but willadsorb as dioxygen at -203°C on aNi(111) surface if some nickel atoms arereplaced with gold. Indeed, a real cata-lyst consists of small gold crystallites, 2-4 nm in diameter, prepared by aque-ous deposition precipitation of a solublegold precursor on oxide support underspecific conditions. Large gold particlesare inactive, residual chloride is a poisonand nitrate is a promoter. Water vapourin the feed gases is essential for highactivity.7 Different studies have pro-

posed conflicting evidence that Au0,Au(CO) complex, AuOH, or Au(OH)3distributed at metal/support interfacialor defect sites are the true active site.8

In any case, the commercialprospects of such a catalyst are brightand have met success, for example, inpurifying the ‘dirty’ hydrogen streamsused for fuel cells by selective oxida-tion of carbon monoxide, a fuel cellcatalyst poison, present in the feedgas with O2, CO2 and N2. In severalstudies, at least 99.5% of the CO hasbeen removed with minimal oxida-tion of hydrogen. One such catalyst is3wt% Au/TiO2.9 Gold catalysts in res-piratory protection devices effectivelyremoved CO by oxidation and aremore effective in the presence ofmoisture, whereas previous catalystsexperienced rapid deactivation.

A number of other target applica-tions are currently under intense inves-tigation, for which gold and sometimesgold alloy heterogeneous catalysts havedemonstrated some unique promise inthe laboratory. These include the epox-idation of propene to propene oxide,the oxidation of alcohols to aldehydesand ketones, the oxidation of glucose togluconic acid, the oxidative addition ofmethanol to acrolein to form methylacrylate, the oxidation of cyclohexaneto cyclohexanol and cyclohexanoneand the direct oxidation of hydrogenand oxygen to hydrogen peroxide.7,10

At the current intense rate of scientif-ic study, some of the gold stored inbank vaults around the world is sure toultimately find its way into productivecatalytic industrial processes in the nextfew years.

References:1. L. Hintermann & A. Labonne, Synthesis2007, 1121-1150 2. D.J. Gorin & F.D. Toste, Nature 2007,446, 395-403 3. J.H. Teles, S. Brode, & M. Chabanas,Angew. Chem. Int. Ed. 1998, 37, 14154. D.J. Gorin, B.D. Sherry, & F.D. Toste,Chem Rev. 2008, 108, 3351-33785. A. Furstner & P.W. Davies, AngewandteChemie 2007, 46, 7896-7936

6. P. Mauleon, R.M. Zeldin, A.Z. Gonzalez,& F.D. Toste, J. Am. Chem. Soc. 2009, 131,6348-63497. S.K. Hashmi & G.J. Hutchings,Angewandte Chemie 2006, 45, 7896-79368. G.J. Hutchings, Dalton Trans. 2008,5523-55369. South African Patent Appl., 2006, 112010. G.C. Bond, C. Louis, & D.T. Thompson,Catalysis by Gold, Imperial College Press,London, 2006

For more information, pleasecontact:Dr Ephraim S. HonigChief Operating OfficerStrem Chemicals7 Mulliken WayNewburyport, MA 01950-4098USATel: +1 978-499-1600E-mail: [email protected]: www.strem.com

n-Bu

N3

n-Bu

N N2+

[Au]Bu

Bu

N

[Au]+Bu

BuH

NH

Bu

Bu

1,2 H shift x2

PPh3AuCl

AgSbF6

•

MeO2C

MeO2C

AuL

+

MeO2C

MeO2C

+LAu

MeO2C

MeO2C

MeO2C

MeO2C

5

6

Ligand 5 : 6t-Bu2(biphenyl)P 4: 96

(1,3-Bis(iPr)imidazol-2-ylidene)AuCl 7: 89

Ph3P 67: 33

(PhO)3P 100: 0+ LAuCl + AgSbF6

A

B

Figure 2 - Cascade involving gold carbenoid

Figure 3 - Ligand-controlled reactivity

Strem.qxp 10/3/10 09:50 Page 16

9 – 10 June 2010Messe BerlinBerlin, German

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Dr Pete Jackson, CEO of Reaxa, considers some of the latest developments and benefits ofpolymer-immobilised catalysts

Catalysts

Catalytic chemistry nowaccounts for almost one thirdof the chemical transforma-tions undertaken in the preparation ofdrug candidate molecules (Table 1).However, the power and potential ofprecious metal catalysis is not always agood fit with the challenges createdby ever more innovative and potentdrugs, including safety assurance topatients and affordability for health-care budget holders.

The critical imperative of safer,faster and cheaper drug productionthrows up a whole raft of manufac-turing issues. And there are many toaddress, as complex new drugssteadily increase the manufacturingchallenges, notably complexity,compliance, decreasing scale andsustainability.

Issues to overcomeThe latest drugs typically requiremore steps, with more difficultchemistries and shorter timescales.Traditionally, process chemists wouldhave a window of perhaps sixmonths before needing to supplymaterial for pre-clinical development.Today’s multi-stage syntheses andhighly complex molecules processput R&D capacity under far greaterpressure.

Moreover, a tighter regulatoryframework is bringing an increasedlevel of manufacturing controls,reduced levels of contaminants (Table2) and the need to eliminate potentialgenotoxic impurities (PGIs).

The FDA’s Guidance for Industrynotes that, although genotoxic andcarcinogenic properties can beacceptable for some APIs, dependingon clinical circumstances (for exam-ple, cancer chemotherapies), impuri-ties in drug substances and drugproducts generally do not have bene-ficial effects and may impose a riskwithout associated benefit. Manufact-urers should therefore strive toachieve the lowest technically feasiblelevels of such impurities and/or levelswith no significant cancer risk.

In addition, demand for lower vol-umes of more complex, more potentdrugs means more sophisticated con-tainment and optimised productioninvestment, increasingly in the form ofmulti-purpose ‘plug and play’ manu-facturing plants. And, last but not least,in terms of its environmental loading,the pharmaceutical processing andmanufacturing sector still has far to go.

By way of illustration, DelftUniversity of Technology uses an ‘E fac-tor’ to measure the efficiency of various

chemicals industries, in terms of kgs ofwaste/kg of desired products. Bulkchemicals generally have an E factor of


Catalysts

applied to metal species includingPd(0), Pd(II), Pt(0) and Os(VIII).

The chemical transformations facili-tated by the cost effective use ofimmobilised catalysts can lead tooverall process resource and cost sav-ings to industry:

• Process chemicals: A reduction ofup to 50% in process costs, materi-als and solvents can be achieved byreducing metal usage and contami-nation in products and on plant thatrequires purification by solventwashing methods. In associationwith the use of immobilised cata-lysts, further reductions in processcosts can be realised from their facil-itation of new drug productionprocesses, such as flow processing.

• Waste reduction: Reducing liquideffluent and solid waste requiringincineration lowers the potential forthe emission of CO2 or otheratmospheric pollutants.

• Precious metal reuse & recy-cling: Reduction in the demand forscarce precious metal resourcesstems from the immobilisation ofthe metal in a form which is easy toseparate after use. This facilitates thereuse of the catalyst, aids the recov-ery of spent catalyst and increasesthe proportion of metal recycled.

• Energy consumption: A directreduction in energy usage comesfrom the lower process temperaturesassociated with improved catalyticprocesses and indirect reduction byavoiding the high-volume incinera-tion of process waste and the recov-ery or refining of precious metals.

Case studiesReaxa’s latest and tenth catalyst to beintroduced, Ni(0) EnCat, is a non-pyrophoric and therefore safer alter-native to Raney or sponge-type nickelcatalysts for use in hydrogenationreactions. It is currently on trial with amajor pharmaceuticals company,which has completed batch trials at20 and 100 kgs scale.

Ni(0) EnCat offers an alternative forup to 20% of the pharmaceuticalhydrogenation catalysts market. Themain application in this field is thereduction of a nitrile group to anamine. Three cases can be cited, instatin, GABA and sartan chemistry.

One method of synthesising theanti-cholesterol drug atorvastatininvolves the formation of a side chaincontaining an amine functionality(Figure 1a). Ni(0) EnCat has beensubstituted into the process in place ofa sponge nickel catalyst. Using thesame catalyst loading, the EnCat reac-tion proceeded to give a 5% yieldimprovement.

Further recycling studies haveshown that the EnCat-encapsulatedcatalyst remains active in subsequentreactions, though an increase in reac-tion time is required to maintain yieldsat the higher level. Alternatively, thecatalyst can be ‘topped up’ after eachrecycle to maintain activity. This com-pares favourably with recycling exper-iments using sponge nickel catalystswhere a dramatic drop in activity andyield is seen following the first recycle.

Another application of Ni(0)EnCathas also been evaluated in the syn-

thesis of a class of commerciallyimportant compounds obtained fromnitrile precursors (Figure 1b). Initialstudies using it in an aqueous reactionsystem showed that optimising thereaction temperature led to a markedimprovement in conversion and areduction in the nickel loading tobelow 4%, compared to the existingsponge nickel catalyst system, whichwas over 10%.

With further process optimisation,45°C was confirmed as the optimumtemperature for running the reac-tion, taking into account the processyield, economics and operationalfactors.

Analysis of the metal content byICP showed nickel contamination of


Dr Christoph Krinninger of Chemetall presents new bases with enhanced properties

Catalysts

The preparation of functionalised aryl and het-eroaryl organometallics via directed ortho-metallation (Figure 1) has found many appli-cations in recent years. BuLi, LDA and TMP-Li arefrequently used as bases for this transformation.

However, these highly reactive bases, like theresulting organolithium species, have limited com-patibility with other functional groups in the sub-strate molecule.1,2 This results in side reactions. Inaddition, cryogenic reaction conditions are frequent-ly required to obtain high yields.

Replacing the lithium with magnesium by usingbases like magnesium diisopropylamide or Hauserbases with the general formula R2N-MgCl improvesthe functional group tolerance. However, to achievehigh conversions it is usually necessary to use alarge excess of these bases, which complicates sub-sequent quenching reactions with electrophiles; upto 10 equivalents of electrophiles may have to beused.3-5

The reactivity of the Hauser Base TMPMgCl/LiClcan be dramatically improved by the addition byLiCl. This additive improves the solubility and kinet-ic basicity of the base by lowering the aggregationstate. Thus, the new mixed lithium and magnesiumbase TMPMgCl/LiCl allows a fast and selectivemagnesiation of aromatic and heterocyclic com-pounds.6

Recently published crystal structures of magne-sium amides with and without the presence of lithi-um by Mulvey and co-workers provide an explana-tion for the synergistic effect observed between themagnesium and the lithium. The bimetallic ate char-acter (Li+MgR3-) of the TMPMgCl/LiCl could be thekey factor for the enhanced reactivity of the newbase.7,8

Directed ortho-metallation with a lithium amidebase results in the formation of the thermodynami-cally favoured product. Hence, the regioselectivityobserved in the lithiation of electron-deficient aro-matics and heteroromatics is determined by anionstability rather than by the rate of deprotonation.

This means that the co-ordination aspect of thelithiation may be secondary in importance to theelectron-withdrawing effect of the substituents. Anexample is the metallation of 3,5-dibromopyridine.

In the case of deprotonation with LDA at cryo-genic conditions, the lithiation occurs at the mostacidic 4-position. When using the new baseTMPMgCl/LiCl at 25°C, kinetic metallation isachieved at the 2 position.6,9

Yamamoto described the ortho-directed lithia-tion of 2,4-dimethoxypyrimidine with TMPLi.

Deprotonation took place at the 5-position. Thechelating effect of the methoxy group leads to thethermodynamically more stable species.

When using TMPMgCl/ LiCl at 25°C, the kinet-ic 6-magnesiated product can be obtained.Trapping the resulting Grignard reagent with ben-zaldehyde furnished the corresponding alcohol in81% yield. Remarkably, the reaction of 2,4-dimethoxypyrimidine in the presence of TMSCl inTHF at -100°C with TMPLi also leads to the kinet-ic product.10,11


Knochel-Hauser bases for selectiv

DG

H

FG

DG

M

FG

DG

E

FG

RM E+

DG = directing groupFG = functional groupM = Li, Mg, Zn

CO2Et

Cl

CO2Et

Cl

CN

CO2Et

Cl

CNEtO2CTMPMgCl · LiCl

(1.2 eq.) 0˚C, 6 hours

TsCN

TMPMgCl · LiCl(1.5 eq.) -20˚C, 5 hours

EtOCOCN

TMPMgCl · LiCl(1.2 eq.) -50˚C, 30 minutes

ZnCl2 (1.2 ep.)Pd(PPh3)4 (2 mol%)

EtOCOCl

CO2Et

Cl

CNEtO2C

EtO2C

CO2Et

Cl

CNEtO2C

EtO2C

TMPMgCl · LiCl(1.5 eq.) -50˚C, 1.5 hours

TsCN

CN

78% 60%

83% 80%

N

CHO

Me

N

CHO

Me

Zn2 N

CHO

Me

71%

TMP2 Zn(0.55 eq.)

THF, 25˚C, 45 minutes CuCn · 2 LiCl (5 mol%)

Br

N

O2N

ClN

NO2Cl

Zn2

N

NO2Cl

80%

TMP2 Zn(0.55 eq.)

THF, 25˚C, 1.5 hours CuCn · 2 LiCl (5 mol%)

Br

Figure 1 - Directed ortho-metallation reaction

Figure 3 - Zincation of highly functionalised heterorenes

Figure 2 - Multiple magnesiation of a benzene derivative

Chemetall.qxp 10/3/10 09:51 Page 20


Catalysts

As well as an enhanced kinetic basicity com-pared with TMP-MgCl, TMPMgCl/LiCl alsoshows an increased functional group tolerancecompared with the lithium amides.

Figure 2 shows a multiple functionalisation ofethyl-3-chlorobenzoate.12 Successive magnesia-tions with TMPMgCl/LiCl and quenching with anelectrophile at reasonable reaction conditions canbe used to synthesise a hexa-substituted benzene.The presence of an ester group is tolerated. Thefunctional groups not tolerated in the presence ofTMPMgCl·LiCl are nitro groups and aldehydes.

Bis-TMPZn/2MgCl2/2LiCl, another base with out-standing properties, was developed in 2007 byKnochel et al.13 Sensitive functional groups, such asesters, aldehydes and nitro groups, are tolerated dur-ing the metallation reactions. The role of the LiCl is toimprove the solubility of the base, MgCl2 increasesthe reactivity and zinc is essential for the high func-tional group tolerance. It should be noticed that bothTMP-moieties are used in ortho-metallation reactions.

Figure 3 shows the zincation of a formyl-substi-tuted indole, which is complete within 45 minutesat 25°C. The polyfunctional pyridine is zincated byBis-TMPZn/2MgCl2/2LiCl at the 4-position, whichmeans that in this case the directing group is the

nitro functionality. A subsequent allylation reactiongives the trisubstituted pyridine in 80% yield.

Chemetall is the owner of the correspondinglicences and is currently developing large-scale syn-theses of the required reagents. The TMPMgCl·LiClis already available as a 20% solution inTHF/toluene; the Bis-TMPZn/2MgCl2/2LiCl isunder investigation and will be scaled up soon.

ConclusionNew magnesium and zinc amide bases readily metal-late a wide range of aromatic and heterocyclic sub-strates. These new bases provide several benefits forortho-metallation reactions in comparison to conven-tional techniques. They exhibit enhanced kinetic reac-tivity and a high functional group tolerance and thereactions can be performed in ambient conditions.


selective deprotonation reactions

For more information, please contact:Dr. Christoph KrinningerChemetall GmbHTrakehnerstraße 3 D-60487 Frankfurt-am-MainTel: +49 69 7165 2587E-mail: [email protected]: www.chemetalllithium.com

References:1. P. Knochel, H. Leuser, Z.-L. Gong, S. Perone & F.Kneisel, in Handbook of Functionalised Organometallics,Wiley-VCH, Weinheim, 2005, 2512. M. Schlosser, E. Zohar & I. Marek in Chemistry toOrganolithium Compounds, Wiley, New York, 2004, 4353. M.-X. Zhang & P.E. Eaton, Angew. Chem. Int. Ed.2002, 41, 21694. Y. Kondo, Y. Akihiro & T. Sakamoto, J. Chem. Soc.Perkin Trans. 1 1996, 23315. P.E. Eaton, C.H. Lee & Y. Xiong, J. Am. Chem. Soc,1989, 111, 80166. A. Krasovskiy & P. Knochel, Angew. Chem. Int. Ed.2006, 45, 29587. P. Garcia-Alvarez, D.V. Graham & E. Mulvey, Angew.Chem. 2008, 120, 1-48. E. Mulvey, Acc. Chem. Research 2009, Vol. 42, 743-7559. Y.G. Gu & E.K. Bayburt, Tetrahedron Lett. 1996, 37,256510. M. Mosrin & P. Knochel, Organic & Biomolecularchemistry 2008, 6, 323711. A. Wada & J. Yamamoto, J. Heterocycl. Chem.1990, 27, 183112. B.W. Lin & P. Knochel, Org. Lett. 2006, 8, 567313. S. Wunderlich & P. Knochel, Angew. Chem. Int. Ed.2007, 46, 7685

N

CHO

Me

71%

NO2

80%

Royal Society of Chemistry Symposium

Elements of Success9 - 10 June, 2010Messe Berlin, Germany

The programme includes: Recent Advances in Fluorination Technology for Custom Synthesis at Saltigo, Wolfgang Ebenbeck, Saltigo GmbH, Germany;Access to Poly-Fluorinated Building Blocks via ElectroChemical Fluorination, Andrea Missio and Maurizio Bertola, Miteni SpA, Italy; Efficient Synthesisof Fluorinated Intermediates for the Agrochemical and Pharmaceutical Industry, Michael Quirmbach, Solvias AG, Switzerland; Sulfur eSSential for Life,Gert De Coster, Sumitomo Chemical Europe representing Sumitomo Seika, Belgium; Sulfur Trioxide Amine Complexes: Versatile Reagents in Organic Synthesis, Jörg Schrickel, CABB AG, Switzerland; Products from Thionyl Chloride tbc, Speaker to be announced, Transpek, London, UK; Lithium and Boron– Two Elements of Success in High-Performance Fine Chemicals Production, Sven Schroeter, ArchimicaiGmbH, Germany; Tools for Organic Synthesis- New Reagents for Lithium Assisted Deprotonation and Addition Reactions, Peter Rittmeyer, Chemetall GmbH, Germany; Cryogenic LithiationReactions for the Production of Starting Materials for Transition Metal Catalyzed Reactions, Adriano Indolese, Rohner AG, Switzerland; Title and Speakerto be Announced, Dottikon Exclusive Synthesis, Switzerland, and Boronic Acids Manufacture at Industrial Scale, Dominique Delbrayelle, Minakem, France.

Programme

The 2010 Royal Society of Chemistry Symposium, Elements of Success, organised by the Speciality Chemicals Sector of the RSC, will highlight recent advances in fluorine, sulfur, boron and lithium chemistry in the manufacture and commercial development of speciality chemicals. This two day international symposium will be held in conjunction with the Chemspec Europe and Chemsource Exhibitions organised by Quartz Business Media.

Delegates will be able to pick and choose which lectures they attend. Further details are available on-line atwww.rscspecialitychemicals.org.uk, where programme updates will be posted, or at www.chemspeceurope.com.

Contact: Dr. Ruth M. Lane Tel/Fax: +44 (0)1928 788071 E-mail: [email protected] www.rscspecialitychemicals.org.uk

Registered Charity Number 207890

Free

Attendan

ceFreeAttendance

Chemetall.qxp 10/3/10 09:51 Page 21


Catalysts


Scavenging for palladiumPasi Kauppinen and Stephanie Phillips of Johnson Matthey illustrate the use of Smopex

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