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Keeping Business Eyes On The Prize

Small firms making boron reagents compete to supply materials for popular coupling reaction

by Ann M. Thayer
April 4, 2011 | A version of this story appeared in Volume 89, Issue 14

Credit: University of Michigan Health System
BoroPharm’s Paul Herrinton works at the company’s site within the University of Michigan’s North Campus Research Complex.
Credit: University of Michigan Health System
BoroPharm’s Paul Herrinton works at the company’s site within the University of Michigan’s North Campus Research Complex.

Six months ago, the 2010 Nobel Prize in Chemistry went to three scientists for their creation of cross-coupling reactions. Among these reactions, the Suzuki-Miyaura coupling, a carbon-carbon bond-forming reaction first published in 1979, has moved from the university lab to the factory floor in the past 15 years. With the help of a new generation of boron-containing reagents, it has become a popular route to pharmaceutical compounds.

Pharma chemical manufacturers have latched onto Suzuki couplings for many reasons. “It is such a useful, general reaction that is easy to run, and the chemistry just keeps improving,” says Dennis Hall, a University of Alberta chemistry professor who is editing the second edition of a comprehensive monograph on boronic acids. He calls the coupling reaction one of the top in medicinal chemistry for making C–C bonds.

Saltigo, a German custom synthesis firm that uses cross-coupling reactions, says it receives dozens of inquiries about them every year, and the number continues to rise. These reactions have made the synthesis of large, complex molecules economically accessible, the firm points out.

In particular, the Suzuki coupling offers many advantages. Its tolerance of a variety of functional groups is one advantage, and high regio- and stereoselectivity are others. In addition, it can be run under mild conditions and generates easily removed inorganic by-products.

The palladium-catalyzed Suzuki reaction couples an organoboron compound, usually a boronic acid or ester, with an organohalide or triflate. Because the result hinges on the structure of the two building blocks, modifying them has expanded the reaction’s scope and versatility. “You come across examples in the literature that were unthinkable 10 to 15 years ago,” Hall says.

Seeing an opportunity, several start-up companies specializing in boron chemistry, often with university ties, are making building blocks available. They and more established firms expect the business to grow as these boron reagents become critical to large-scale syntheses.

“The artistry behind medicinal chemists’ thinking starts as they consider the new structures that they could build,” explains Todd Zahn, chief executive officer of Boro­Pharm. To aid the creation of these new structures, the Michigan-based firm has an R&D team that looks for ways to produce novel boron compounds, some of which can’t be made by traditional means, he adds.

Older methods tend to be harsh or technically demanding. Traditional routes to boronic acids involve Grignard chemistry or low-temperature reactions with lithiated compounds. “You can’t get to some structures easily, affordably, or environmentally safely with some traditional methods,” Zahn says.

BoroPharm was launched in 2005 by Michigan State University professors Robert Maleczka and Milton Smith. In 2008, they won a Presidential Green Chemistry Challenge Award for their C–H activation/borylation method, which allows direct construction of boron compounds under mild conditions while generating less waste. Using this approach and others licensed or developed in-house, the company now offers a catalog of several hundred boronates and other compounds, along with custom synthesis services.

Having outgrown space in East Lansing, BoroPharm last year became the first commercial tenant of the University of Michigan’s North Campus Research Complex, a former Pfizer facility in Ann Arbor. “Our objective was to become the most comprehensive boronate intermediate supplier out there,” Zahn says. The company now has “scale and scope,” he adds, and is able to offer a variety of compounds in gram to metric-ton quantities.

Manufacturing on the lab scale, France’s BoroChem has a catalog of more than 1,000 organoboron and other compounds, including bioactive boron-based molecules. “We prepare compounds in research quantities and have collaborations to make larger quantities,” says Alexandre Bouillon, who founded the firm in 2005 after completing his doctorate at the University of Caen. He hopes the company will be able to add its own production capacity soon.

For now, he says, “we specialize in difficult-to-synthesize and hard-to-stabilize compounds.” BoroChem doesn’t attempt to compete with low-cost producers in Asia that make more standard, large-volume compounds, he says. At the same time, it does go head-to-head with other start-ups and major research chemical firms, such as Sigma-Aldrich, as well as building-block suppliers such as Combi-Blocks and Frontier Scientific. Bigger producers of boron intermediates that supply larger quantities—including AllessaSyntec, Archimica, BASF, and Optima Chemical—also do some custom synthesis.

“This is a niche market, with big producers and small companies specializing in innovative compounds, but I believe there is enough space for both strategies,” Bouillon explains. BoroChem, like BoroPharm, was created around synthetic methods licensed from academia and then further developed in-house. “Each company has its own patented method to prepare boron derivatives,” he adds.

Before either BoroPharm or BoroChem emerged, Boron Molecular was spun out of Australia’s Commonwealth Scientific & Industrial Research Organisation in 2001 to make novel boron compounds. It has a license to the patented work of CSIRO scientist Sebastian Marcuccio, who in 2005 founded Advanced Molecular Technologies, another supplier of organoboron compounds.

To move beyond catalog sales and position itself to support scale-up and early commercial work for customers, Boron Molecular opened a 630-L plant in late 2009. This February, Xceed Capital, which had owned Boron Molecular since 2004, sold it to the polyvinyl chloride compounder Welvic Australia for about $1.5 million. At the time, Boron Molecular reportedly had annual sales of about $3 million.

Meanwhile, AllessaSyntec, an in-house service unit of Hoechst until 1997, focuses on low-temperature and organometallic chemistry. Independent since 2004, the firm uses that expertise to produce specialty boronic acids and esters at two plants in Frankfurt. “We started producing boronic acids in the early 1990s and have in-house capacity up to 1,000 L,” says Steffen Partzsch, director of sales and marketing.

About half of AllessaSyntec’s business is related to boronic acids, which it can make in quantities of tens of tons per year. The company designed its own reactors for precise temperature control, allowing clean reactions with high selectivity and yield, Partzsch explains. The required know-how and capital investment are barriers to entry for competitors, he believes.

Archimica also has large-scale low-temperature and organometallic chemistry capabilities that it applies to making boronic acids. In a presentation at the Informex trade show in February, the company said it has been making highly functionalized and heterocyclic boronic acids in multi-metric-ton quantities for certain customers.

Archimica has also developed routes to alkyl and vinyl boronic acids, derived from its work with Victor A. Snieckus at Canada’s Queen’s University, using inexpensive starting materials via in situ hydroboration. And it has developed methods to use these reagents in subsequent coupling reactions.

Indeed, for many companies that already manufacture the reagents, the next logical step is conducting the cross-coupling reaction to produce more advanced intermediates for customers. Archimica, for example, boasts about having completed the first industrial-scale Suzuki coupling in 1990. And Saltigo makes many of the boronic acids it needs for the Suzuki reactions it runs.

AllessaSyntec and BoroPharm have moved in this direction as well. “We know how these boronate species are going to react and understand the sensitivities and stability issues behind them,” Zahn says. “We can move to the coupling function quickly, and there can be cost savings if steps can be cut out of the process.”

Regardless of the party carrying them out, Suzuki couplings can shorten otherwise multistep routes by simply joining molecular fragments without having to worry about functional groups. “When you do a Suzuki coupling, the regiochemistry is guaranteed by the placement of the halide on one reactant and the boronic acid on the other side,” the University of Alberta’s Hall explains. Because of this factor and the fact that conditions and catalysts can usually be found to make any combination work, the reaction has become predictable and reliable.

This assuredness means that pharma chemical makers can pick and choose compounds from catalogs with the confidence that they’ll probably work, Hall explains. And if a compound doesn’t exist, companies can spend the money to have it made.

With the proliferation of suppliers, prices have come down. Ten years ago, starting materials such as bis(pinacolato)diboron were expensive. “Now you can buy it by the bucket, and it has given us a much greener way to make boronic acids and esters,” Hall says.

Because Suzuki couplings offer “almost endless possibilities, the limitation becomes the commercial availability of the building blocks,” Hall says. “But you’d guess it is a good business because there are many more companies and so many boronic acids and esters commercially available now.”

In order to help companies create libraries for lead development, BoroPharm launched BoroKits last fall. The preweighed kits contain catalyst and various functional boronates. “The customer can just add their molecule of interest and then quickly ramp up their library synthesis,” Zahn says. Custom kits also are available.

Suzuki coupling wouldn’t have advanced without simultaneous improvements in catalyst design and variety, most of which also have come from academic labs. Mastering the reaction for industrial use depends on getting residual palladium to acceptable levels in the final products, Bouillon explains. More active catalysts have been a major factor in this regard.

Since the start, boronic acids have had the reputation of being unstable or difficult to obtain in pure state, according to Bouillon. Although many are shelf-stable solids, the issue often is that they are unstable under the Suzuki reaction conditions and decompose before the coupling proceeds. To address these issues, boron compound makers supply a variety of alternative structures.

“There are many new forms of boron derivatives, whereas 20 years ago it was only boronic acids,” Bouillon says. “With new methods for synthesizing boron derivatives, people have a choice depending on the chemistry they want to perform.”

Boronic esters were an initial step forward when the corresponding acid was unstable or poorly soluble in the reaction solvent. Another approach has been to use trifluoroborates, which tend to be more stable than their boronic acid counterparts. The University of Pennsylvania’s Gary A. Molander, an adviser to BoroChem, is among the scientists who have led the development of trifluoroborates.

Similarly, Martin D. Burke at the University of Illinois, Urbana-Champaign, developed chemistry using N-methyliminodiacetate to protect otherwise unstable compounds and release boronic acid intermediates slowly as the coupling reaction proceeds. Among the several hundred boron compounds Sigma-Aldrich offers for Suzuki couplings, it makes and sells MIDA-boronates through a licensing agreement with the university.

Suppliers and custom manufacturers say the largest markets for boron reagents are pharmaceutical and agrochemical intermediates and electronic materials, whereas consumer products is an emerging area. “We see the market growing because of the success of the Suzuki-Miyaura coupling, not only in the pharma industry, but also in other industries that are catching on as more chemists use it as a way to make new products,” Zahn says.

People in the business already see a positive impact on chemical production efficiencies. “With the convenience of the Suzuki coupling and the accessibility of the boronate species, I don’t see it going away,” Zahn says. “The approach is only becoming more and more popular.”


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