COVER STORY
WHEN COOPERATIVE RIVALRY WORKS Two fine chemicals companies separately but cooperatively bring key technology to market A. M A U R E E N R O U H I , C & E N
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OR THE PAST TWO YEARS, RHODIA
Pharma Solutions and Bayer Chemicals AG, now Lanxess, have been developing a chemistry that is of interest to the pharma ceutical industry The companies are stiff competitors as providers of technology, process development, and custom syn thesis services to drug companies. But by working in parallel to achieve a common technological goal, they are multiplying ac cess to an enabling technology and bring ing competition into the market, which could only benefit customers. The parallel development efforts are fo cused on the palladium-catalyzed forma
tion of carbon-nitrogen bonds, chemistry that was invented in the mid-1990s in pro fessor Stephen L. Buchwald's lab at Mass achusetts Institute of Technology Through this reaction, aryl halides are converted to arylamines. The reaction is also referred to as the Buchwald-Hartwig reaction be cause Yale University chemistry professor John F. Hartwig reported similar chem istry at almost the same time. Rhodia Pharma Solutions holds an ex clusive license from M I T to practice the Buchwald chemistry The firm granted an exception to its exclusivity to allow M I T to grant a license to Bayer Chemicals to use the chemistry for custom synthesis and
THE CHEMISTRY is versatile and superior to existing technologies used to convert aryl halides to aniline derivatives, and it has the potential to generate new com mercially important molecules, says Michel Spagnol, vice president for sales and marketing at Rhodia Pharma Solu tions. Although the chemistry was initial ly developed for the construction of aryl-
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to scale up the production of ligands for the process. Independently each compa ny is commercializing the technology and offers it to customers. Both companies share the goal of offering customers time ly and flexible access to a technology that affords cost-effective routes to commer cially important compounds. Even in the early stages of drug develop ment, this Buchwald chemistry "is playing an increasingly important role in the iden tification and development of drug candi dates throughout the pharmaceutical in dustry" according to David R. Kronenthal, director of process R&D at Bristol-Myers Squibb. Many compounds in the drug de velopment pipelines have bond connections that can be made with this method.
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nitrogen bonds, it also can be applied to the formation of carbon-carbon and car bon-oxygen bonds. The market for mole cules to which this technology can be ap plied is growing rapidly According to Buchwald, Bayer Chemi cals became aware of the chemistry after MIT had granted exclusive license to the company formerly known as Chirex, which Rhodia later acquired. Chirex had been figuring out how to commercialize the chemistry when it learned through Buch wald that Bayer Chemicals also recognized the commercial potential. A three-way agreement was negotiated among MIT, Rhodia, and Bayer Chemicals. The companies agreed to develop the technology separately To enable sharing of technical information with each other and the wider chemical community, they
identified model compounds on which the technology would be applied. Wilhelm Stahl, head ofpharmaceutical marketing at Lanxess' fine chemi cals business unit, points out that the model compounds are not related to any spe cific customer request. Concurrent with the work on model compounds but com pletely separate from the collaboration, RhodiaPharmaSolutions and Lanxess are each separately applying the chemistry to customer projects. Those projects, both companies emphasize, are carried out under strict confidentiality
sured of multiple sourcing and will benefit from the competition between the two. Separately Rhodia Pharma Solutions and
"One team's success motivates the other team. It's more that everybody wants to contribute rather than one team needing to be better than the other."
THE TWO COMPANIES compete for the same customers, but neither one knows who is talking to DOABLE whom. Both are aware Using model compounds, Rhodia pavesa path of the aversion of to heterocycles pharmaceutical comH C 5 6 v^CoHs panies to single sourcing, which is a big N> V concern with use of NH9 proprietary technology But when two independent providers have equivalent knowhow and expertise in 37% HCl ^ H5C6 \ / C A H ! the proprietary techNitrogen nology and customers heterocycles are free to negotiate NH3ÇI with one or the other, customers can be as-
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Lanxess have begun disclosing results of their development efforts. For example, at the 10th International Conference on Organic Process Research & Development, organized by Scientific Update and held in July in Vancouver, Lanxess R&D chemist Guido Giffels described the scale-up ofthe synthesis of one of the Buchwald ligands. Dubbed Dave-Phos, this ligand can now be prepared on a scale of tens ofkilograms. Giffels also reported that Lanxess has applied Buchwald's coupling chemistry to a customer problem. Using a palladiumDave-Phos catalyst, Lanxess has successfully joined a chiral tertiary amine to a substituted aryl halide with complete retention of stereochemistry The reaction has been practiced at a 500-kg scale. At the same conference, Rhodia process chemistry group leader Laurent SaintJalmes described development work to scale up the catalytic conversion of aryl chlorides to aryl hydrazones. These products are precursors to aryl hydrazines, which are precursors to many nitrogen heterocycles. Saint-Jalmes also reported the
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C & E N / S E P T E M B E R 6, 2 0 0 4
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COVER STORY successful scale-up of two other Buchwald ligands, dubbed Me-Phos andX-Phos. "Things moved much more rapidly than I expected," Buchwald says. That's because the technical teams from the two companies share information, understanding, and know-how gleaned from their work on model compounds. Each team has access to Buchwald.
take that reaction and work out all the many problems so it can be applied to real-world chemistry on increasingly larger scales." Buchwald says he is also pleased that "the exact strategies and the way of going about things" by the two companies are different. That means the chemistry is versatile; one does not need to follow a rigid pathway to be successful with it, he explains. SCALED UP Shared technological goals are A DISCOVERY at either company Lanxess and Rhodia have developed commercial strong incentives for the coopwould be transmitted to Buchroutes to three ligands eration between Rhodia Pharma wald and to the chemists at the Solutions and Lanxess. In this other company But because the case, transparency also has been teams were working independa critical success factor. ently and in their own style, their "The key to having this colefforts had a synergistic effect. If laboration work is that the peoone team had a problem that the ple trust each other; otherwise other already had solved, time was they would withhold informanot wasted reinventing the wheel. Me-Phos tion," Buchwald says. "Everyone The chemists involved have difhas been sharing their results, ferent backgrounds and personalCy = cyclohexyl X-Phos tricks, and insights unless bound ities. Uli Scholz, who leads the by confidentiality obligations. Lanxess team, is still relatively One team's success motivates the other they are now The progress made in the past fresh from being a student and a postdoc. team. It's more that everybody wants to two years was much greater than I would Gerard Mignani leads the Rhodia team. He contribute rather than one team needing have thought possible. It's one thing to disis a seasoned R&D chemist with what Buchto be better than the other." • cover a reaction, and it's another thing to wald says is his own unique way of "doing things." Buchwald wondered at first if the match would work but quickly saw the commitment of both leaders and their teams. "I was impressed by their incredible tenacity" Buchwald says, given how often the separate teams would get frustrating results and would have to go back to square one. "They just kept going at it to get where
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