When Cooperative Rivalry Works

For the past two years, Rhodia Pharma Solutions and Bayer Chemicals AG, now Lanxess, have been developing a chemistry that is of interest to the pharmaceutical industry. The companies are stiff competitors as providers of technology, process development, and custom synthesis services to drug companies. But by working in parallel to achieve a common technological goal, they are multiplying access to an enabling technology and bringing competition into the market, which could only benefit customers.

The parallel development efforts are focused on the palladium-catalyzed formation of carbon-nitrogen bonds, chemistry that was invented in the mid-1990s in professor Stephen L. Buchwald's lab at Massachusetts Institute of Technology. Through this reaction, aryl halides are converted to arylamines. The reaction is also referred to as the Buchwald-Hartwig reaction because Yale University chemistry professor John F. Hartwig reported similar chemistry at almost the same time.

Rhodia Pharma Solutions holds an exclusive license from MIT to practice the Buchwald chemistry. The firm granted an exception to its exclusivity to allow MIT to grant a license to Bayer Chemicals to use the chemistry for custom synthesis and to scale up the production of ligands for the process. Independently, each company is commercializing the technology and offers it to customers. Both companies share the goal of offering customers timely and flexible access to a technology that affords cost-effective routes to commercially important compounds.

Even in the early stages of drug development, this Buchwald chemistry "is playing an increasingly important role in the identification and development of drug candidates throughout the pharmaceutical industry," according to David R. Kronenthal, director of process R&D at Bristol-Myers Squibb. Many compounds in the drug development pipelines have bond connections that can be made with this method.

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 commercially important molecules, says Michel Spagnol, vice president for sales and marketing at Rhodia Pharma Solutions. Although the chemistry was initially developed for the construction of aryl-nitrogen bonds, it also can be applied to the formation of carbon-carbon and carbon-oxygen bonds. The market for molecules to which this technology can be applied is growing rapidly.

According to Buchwald, Bayer Chemicals 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 Buchwald 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 of pharmaceutical marketing at Lanxess' fine chemicals business unit, points out that the model compounds are not related to any specific customer request.

Concurrent with the work on model compounds but completely separate from the collaboration, Rhodia Pharma Solutions and Lanxess are each separately applying the chemistry to customer projects. Those projects, both companies emphasize, are carried out under strict confidentiality.

THE TWO COMPANIES compete for the same customers, but neither one knows who is talking to whom. Both are aware of the aversion of pharmaceutical companies to single sourcing, which is a big concern with use of proprietary technology. But when two independent providers have equivalent know-how and expertise in the proprietary technology and customers are free to negotiate with one or the other, customers can be assured of multiple sourcing and will benefit from the competition between the two.

Separately, Rhodia Pharma Solutions and 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 of the synthesis of one of the Buchwald ligands. Dubbed Dave-Phos, this ligand can now be prepared on a scale of tens of kilograms.

Giffels also reported that Lanxess has applied Buchwald's coupling chemistry to a customer problem. Using a palladium-Dave-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 Saint-Jalmes 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 successful scale-up of two other Buchwald ligands, dubbed Me-Phos and X-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.

A DISCOVERY at either company would be transmitted to Buchwald and to the chemists at the other company. But because the teams were working independently and in their own style, their efforts had a synergistic effect. If one team had a problem that the other already had solved, time was not wasted reinventing the wheel.

The chemists involved have different backgrounds and personalities. Uli Scholz, who leads the Lanxess team, is still relatively fresh from being a student and a postdoc. Gerard Mignani leads the Rhodia team. He is a seasoned R&D chemist with what Buchwald 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 they are now. The progress made in the past two years was much greater than I would have thought possible. It's one thing to discover a reaction, and it's another thing to 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.

Shared technological goals are strong incentives for the cooperation between Rhodia Pharma Solutions and Lanxess. In this case, transparency also has been a critical success factor.

"The key to having this collaboration work is that the people trust each other; otherwise they would withhold information," Buchwald says. "Everyone has been sharing their results, tricks, and insights unless bound by confidentiality obligations. 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."