Catalysis and Chiral Chemistry Key Topics at Informex

February 16, 2006
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Informex, ORLANDO - Optimizing a synthesis for an active pharmaceutical ingredient (API) or pharma intermediate is a critical part of the pharmaceutical manufacturing process, and several exhibitors at this year’s Informex highlighted their recent advances in catalysis, biocatalysis, and chiral chemistry. Among the developments: Reaxa to launch biotech affiliate. ChiralQuest develops new chiral ligands. BioCatalytics launches new line. Codexis expands directed evolution biocatalysis program with BMS. Chemtura targets organometallic catalysts for pharma manufacturing.

Informex, ORLANDO - Optimizing a synthesis for an active pharmaceutical ingredient (API) or pharma intermediate is a critical part of the pharmaceutical manufacturing process, and several exhibitors at this year’s Informex highlighted their recent advances in catalysis, biocatalysis, and chiral chemistry. Among the developments: Reaxa to launch biotech affiliate. ChiralQuest develops new chiral ligands. BioCatalytics launches new line. Codexis expands directed evolution biocatalysis program with BMS. Chemtura targets organometallic catalysts for pharma manufacturing.

Reaxa plans launch of sister biotech company

Reaxa (Manchester, UK, www.reaxa.com) announced this week it will launch a sister company, Reaxa Biotech. Reaxa Biotech is scheduled to launch in early 2007 and will focus on polymer drug-conjugation, solid-phase synthesis, drug immobilization,and controlled-release polymer technologies. It will complement the company’s current precious metal chemistry and supported reagents operations.

Reaxa was formed from the spinoff of Avecia in June 2005, with a first round of investment from private investors, small institutional investors, and a 21-percent stake from Umicore (Brussels, Belgium), a catalyst manufacturing firm.

"Reaxa is not a custom manufacturing company, but offers specialized process development service to our clients," explains Peter Jackson, CEO of Reaxa. "We have the ability to prove processes up to 20-liter scale before technology transfer back to our clients."

The company also is broadening its portfolio in encapsulated catalyst technology (EnCat catalyst). That technology was originally developed through a joint venture, begun in the mid 1990s, between Professor Steven Ley at Cambridge University, AstraZeneca, Syngenta, and Avecia Pharmaceuticals. The first products, containing immobilized palladium acetate with and without co-encapsulated phosphine ligands, are designed to offer improved processing over traditional homogeneous catalysts and to produce cleaner drug products without metal contamination.

Reaxa successfully scaled up production of Pd (II) EnCat 30 and Pd (0) En Cat NP30 in the fourth quarter 2005. It also has introduced a new Os EnCat product (containing osmium tetroxide) for use in dihydroxylation reactions. It  plans to introduce new nickel and platinum EnCat products in 2006.

Reaxa also is launching five new macroporus scavengers to its QuadraPure range. These products remove metals from pharmaceutical and chemical processes. They are designed as an alternative to polymer fiber and silica-based scavengers. Reaxa developed the products from in-house proprietary resin functionalization technology.

The company also has inked a deal with Biotage AB (Uppsala, Sweden, www.biotage.com), a supplier of tools and technology for medicinal chemistry, under which Reaxa will put its products into Biotage’s flow processing and microwave equipment. In the first quarter, Reaxa will introduce new microwave-compatible EnCat catalysts and QuadraPure scavenging resins prepackaged in a ready-to use cartridge format.

In biopharmaceuticals, Reaxa has launched a new peptide production technology based on 2-mercaptobenzothiazole (2-MBT) for use in small-scale, solid-phase manufacture of peptides. “2-MBT is a cheap, effective and readily available coupling reagent for use in peptide synthesis as an alternative to HOBt (1-hydroxybenzotriazole hydrate),” says Jackson.

ChiralQuest develops new chiral ligands

ChiralQuest Inc. (Monmouth Junction, NJ), a subsidiary of VioQuest Pharmaceuticals Inc. (Basking Ridge, NJ, www.vioquestpharm.com) is making available new chiral ligands on a commercial scale for use in asymmetric hydrogenation.        

ChiralQuest was founded in 2000 based on technology of Professor Xumu Zhang from Pennsylvania State University. He developed a toolbox of chiral phosphine ligands for catalytic asymmetric hydrogenations for use on a variety of substrates, some of which had been historically resistant to facile hydrogenation.

ChiralQuest has five commercially available catalyst ligands, including C3-TunePhos, a member of the atropisomeric aryl bisphosphine ligand family, which provides enantioselectivities and catalytic abilities similar to the widely used chiral ligand BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl).

New on a commercial basis is the third generation of P-chirals ligands, DuanPhos, for the asymmetric hydrogenation of beta-amino ketones to make beta-hydroxyl-amines, beta-acylamino acrylates to make beta-amino acids, and for the hydrogenation of itaconic acids and their derivatives.

This year also marks the first full year of operation for ChiralQuest’s new 40,000-square-foot pilot production facility in Jiashan, China. "The facility allows us to take advantage of low-cost production economics in supplying early-stage intermediates for our catalysts and ligands," says Michael Cannarsa, general manager of ChiralQuest. "In addition, this facility facilitates the large-scale production of chiral intermediates and building blocks for our customers. ChiralQuest recognizes the importance of supplying downstream chiral intermediates in addition to the development of the isolated chiral transformation step," he says. The Jiashan facility complements its kilo-lab facilities in Monmouth Junction, NJ.

ChiralQuest has licensing agreements with several of the large pharma companies, including Merck. It is also part of a R&D and marketing consortium with CSS (Craigavon, Ireland, www.css-almac.com), a provider of contract chemistry services, and IEP GmbH (Wiesbaden, Germany, www.biocatalysis.com), which specializes in using biocatalysts, specifically alcohol dehydrogenases, to make chiral hydroxyl compounds.

BioCatalytics launches new biocatalyst line

BioCatalytics Inc. (Pasadena, CA, www.biocatalytics.com) launched a new biocatalyst line at Informex. The company produces enzymes used in the synthesis of pharma intermediates, active pharmaceutical ingredients (APIs) and drug metabolites.

EREDS is a new line of biocatalysts used for the stereoselective reduction of certain alkenes. BioCatalytics currently offers a line of ketoreductases, which reduce prochiral ketones to single enantiomers of secondary alcohols.

"In addition, we are expanding our custom services, which provide enzyme screening, process development optimization, and analytical support for biocatalytic routes for producing APIs and pharma intermediates," said David Rozzell, president and CEO of BioCatalytics at Informex. The company offers these services from its lab facilities in Pasadena, CA, where it also manufactures its enzymes.

The company is opening up a new European subsidiary, BioCatalytics Europe GmbH, this month in Graz, Austria. The new group will include distribution and warehousing facilities to service the European market. It opened sales and marketing facilities in Graz in 2005.

Last month, BioCatalytics formed a research collaboration with Eucodis GmbH (Vienna, Austria, www.eucodis.com), which provides technologies based on in vivo recombination and somatic hypermutation. BioCatalytics plans to use Eucodis’ recombinatorial methods to create improved enzymes in special reaction classes.

Codexis expands BMS pact

Codexis Inc. (Redwood City, CA, www.codexis.com), which specializes in developing novel synthetic routes to small molecule drugs using biocatalysts, has extended a research agreement with Bristol-Myers Squibb Company (New York, NY, www.bms.com). The pact is focused on improving biocatalyst productivity for an undisclosed product candidate in BMS’ pipeline.

The research pact involves the use of Codexis’ proprietary MolecularBreeding directed-evolution platform, which uses protein and strain engineering technologies to develop biocatalysts (enzymes) for manufacturing pharma intermediates or APIs.

"We use our technologies to develop never-before-seen biocatalysts that can be used to optimize synthetic routes for APIs and pharma intermediates," says Tassos Gianakakos, senior vice president for  business development at Codexis. "For example, the biocatalyst may be used in an asymmetric reaction to dramatically improve the yield and purity of the desired enantiomers. The biocatalytic route also may optimize the process by reducing the number of steps in a synthesis, allow the reaction to be run at milder conditions in terms of pressure or temperature, or reduce solvent usage in a reaction."

Codexis develops and markets APIs and pharmaceutical intermediates made using its proprietary biocatalysts, and in some cases, provides the biocatalyst and process development services to its clients. The BMS collaboration is one of 16 research pacts Codexis has entered into for process R&D. The company has pacts with Pfizer (New York, NY, www.pfizer.com), Sandoz (the generics arm of Novartis AG, Holzkirchen, Germany, www.sandoz.com), Teva Pharmaceuticals (Petach Tikva, Israel, www.tevapharm.com), the fine chemicals company Lonza (Basel, Switzerland, www.lonza.com) and the Indian generic drug companies Arch Pharmalabs and Matrix Laboratories (Hyderabad, India, www.matrixlabsindia.com) as well as Shasun Chemicals & Drugs Ltd. (Chennai, India, www.shasun.com) which recently acquired Rhodia's pharma custom manufacturing activities.   

Chemtura targets pharma manufacturing

On the chemocatalysis side, Chemtura Corporation’s (Middlebury, CT, www.chemtura.com) organometallic specialties (OMS) business unit is strengthening its position in fine chemicals and pharmaceuticals. OMS was launched at the 2005 installment at Informex, and 2006 marks its first year of operation as part of Chemtura. Chemtura, which posted 2005 sales of $3.9 billion, was formed from the 2005 merger of Crompton Corporation and Great Lakes Chemical Corporation. Roughly 20 percent of OMS's customer base is in the pharmaceutical market. 

"We formed OMS in order to have a focus on the requirements of the pharmaceutical industry," says Ulrich Stewen, market development manager, OMS, at Chemtura. "This includes not only selling organometallic catalysts, but also involves providing services for the safe handling, waste treatment, recycling, and purification of these products to support our pharmaceutical customers."

OMS invested roughly $10 million at its manufacturing site in Bergkamen, Germany as part of a multi-year program to modernize infrastructure and to increase production. It shares the site with the German pharmaceutical company Schering AG (Berlin, Germany, www.schering.de) and the US chemical company Huntsman Corporation (The Woodlands, TX, www.huntsman.com). Schering AG staffs roughly 2,000 employees at Bergkamen and Chemtura, 250.

OMS makes organometallic catalysts and reagents used in producing active pharmaceutical ingredients (APIs), and some recent advancements center on their use in asymmetric reactions for making steroselective APIs, notes Stewen. For example, diisobutylaluminum hydride and triisobuytlaluminum are used as selective reducing agents, including reductions for high stereoselectivity, such as in Meerwein-Ponndorf reactions. Trimethylaluminum is used for high selectivity in various methylation reactions and also promotes the selective 1,4-addition to enones and is recommended for Weinreb amidations. Triethylboron is used for controlled and regio-specific alkylations.

Chemtura also manufacturers fluorine and brominated performance products for the pharmaceutical manufacturing market.

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