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Synthesis

Constructing Life Sciences Compounds

Fluorinated building blocks are increasingly used as the basis of valuable active molecules

by Ann M. Thayer
June 5, 2006 | A version of this story appeared in Volume 84, Issue 23

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Credit: Saltigo Photo
Saltigo has direct access to more than 4,000 fluorinated building blocks and procedures for synthesizing more than 24,000 fluoroorganic compounds.
Credit: Saltigo Photo
Saltigo has direct access to more than 4,000 fluorinated building blocks and procedures for synthesizing more than 24,000 fluoroorganic compounds.

COVER STORY

Constructing Life Sciences Compounds

"A very significant fraction of new drugs and agrochemicals have fluorine in them," says William R. Dolbier Jr., professor of chemistry at the University of Florida, because of the unique biological benefits fluorine can impart. And building blocks, or simple fluorine-containing organic molecules, are important, he adds, "because few pharmaceutical and agrochemical chemists have much experience with basic fluorine chemistry."

For the most part, he says, organic chemists don't want to deal with direct fluorination reactions, especially those involving specialized equipment and hazardous reagents. Although an increasing number of more easily handled fluorinating reagents have emerged and are being used by chemists to selectively insert fluorine (see page 15), a popular approach is to start with a fluorine-containing structure as a scaffold for further functionalization.

"It's amazing how many fluoroarenes and fluoroheterocycles can be ordered from specialized suppliers at affordable prices," according to Manfred Schlosser, professor of chemistry at the Swiss Federal Institute of Technology, Lausanne. With further modification, he believes, these molecules can be transformed into useful building blocks for pharmaceuticals and agrochemicals.

In response to growing interest in the marketplace, fine chemicals producers and fluorine chemistry specialists are making a range of fluorinated compounds on a custom basis or as bulk intermediates. Many companies focus on a particular fluorination expertise or operate from a base in fluoromaterials. Other commercial channels are smaller chemistry firms that serve as catalog suppliers of limited quantities and traders that sell, but don't make, lab-scale amounts.

"Fluorinated building blocks are becoming more and more important in the life sciences and represent a class of high-value compounds," says Wolfgang Ebenbeck, head of the fluorine team at Saltigo, the fine chemicals business of Lanxess. "They are an attractive market segment because of their high prices, which are probably comparable to chiral compounds." Saltigo's custom manufacturing unit has a range of large-scale fluorine chemistry capabilities, and its fluorine team offers custom research services for organofluorine compounds.

Saltigo's fluorine chemistry team has more than 40 years of experience. When it was part of Bayer's former central research department, it supplied fluorinated building blocks for crop protection, pharmaceutical, and animal health R&D. Today, it boasts an in-house library of 4,500 fluorinated molecules, many of which are unpublished structures, and plans to create a catalog of 2,500 compounds. It also has experience with more than 24,000 fluoroorganic syntheses. "We have an approach to most classes of fluorinated compounds a customer might want," Ebenbeck says. "We can provide from grams up to kilograms of fluorinated building blocks for drug discovery or preclinical programs."

Similarly, as part of its custom chemical offerings, Solvias supplies tailor-made fluorinated compounds to medicinal chemistry and early drug development customers. "We currently have a database of about 1,500 fluorination reactions carried out in-house," says Marian Misun, project manager for synthesis at Solvias, and can make fluorinated compounds on up to a kilogram scale. The company says it is developing a catalog of fluorine-substituted products that will be available in small quantities.

Customers frequently have worked out a synthetic route and know the fluorinated building block they want, suppliers say, often without revealing the target compound. Others may still be searching for or optimizing fluorine-containing compounds and are happy to find building blocks they didn't know could be made or with different substituents. These options can offer attractive opportunities for improved activity and for circumventing intellectual property positions.

"We have to look for innovative classes of compounds and see what the market demand is or even suggest new structures and compounds," Ebenbeck says. "Inquiries for fluorinated building blocks are getting more challenging, and it is interesting to note that those for agrochemicals are comparable to ones for pharmaceuticals in terms of the complexity of the structures." These building blocks can include, for example, carbocyclic, heteroaromatic, and bicyclic systems, as well as completely new structures, such as tetrafluorobenzodioxanes or difluorocyclopropyl groups as mimics for isopropyl groups.

Competition clearly is heating up, fine chemicals producers say, particularly in supplying simple molecules or traditional chemistries, such as halogen exchange (Halex) for making fluorinated aromatics. "Halex reactions are usually medium-scale batch chemistry that doesn't require very large equipment or large plants," says Ralf Pfirmann, global business director for Clariant Pharmaceutical Fine Chemicals. As a result, many low-cost competitors in China have picked up the technology.

To compete, Clariant, like other producers, no longer makes what Pfirmann calls "easy-to-make fluorinated aromatics based on textbook technology" except to meet specific customer requirements. Instead, companies are specializing in new technologies and trying to use them to make more challenging fluorinated structures. An example is new Halex catalysts to make fluoroaromatics with otherwise difficult-to-obtain substitution patterns.

Clariant also has developed a technology for making trifluoromethylpyridines that avoids highly corrosive and toxic reagents such as SF4, says Andreas Meudt, global head of R&D for Clariant Pharmaceutical Fine Chemicals. The reaction sequence starts with a trifluoroacetic anhydride building block and uses the company's assets in cryogenic chemistry.

Similarly, on the basis of its experience in lithium chemistry, Clariant uses the deprotonation of F- and CF3-containing aromatics to introduce a range of functional groups in the ortho position. "This approach often makes compounds that are not accessible via classical chemistries," Meudt says. "The challenge is the safety of such reactions, as intermediates with Li and a halogen (X) in the ortho position tend to eliminate LiX in sometimes very vigorous decomposition reactions."

On the basis of its review of the market and initial customer requests, Rhodia targeted fluorinated aliphatics as a growth area and launched a program about five years ago to develop radical trifluoromethylation chemistry, says Michel Spagnol, vice president for sales and marketing at Shasun Pharma Solutions, part of the former Rhodia Pharma business. The process has been scaled up to the ton level, and Shasun now supplies CF3-containing aliphatics such as trifluoromethylated alkenes, trifluorobutanol derivatives, and 3,3,3,-trifluoropropanealdehyde derivatives.

Such fluorinated structures can be grafted onto a molecular scaffold to produce different active structures. For example, points out Allen C. Sievert, senior research associate with DuPont FluoroIntermediates, the commercial fungicide Tetraconazole and insecticides Noviflumuron and Novaluron are all fluoroolefin adducts of alcohols or phenols with groups derived from tetrafluoroethylene (TFE), hexafluoropropylene (HFP), and perfluorovinyl ethers, respectively.

DuPont makes all three fluorinated monomers, which it had used largely in its long-standing fluoropolymer business, and other derivatives and building blocks. The company created the fluorointermediates business about three years ago to offer its expertise in organofluorine chemistry in response to growth in customer inquiries, Sievert says. "We pursue opportunities where we feel we have a unique raw material or technology advantage."

The situation is similar at other major companies. Daikin Industries, a fluorocarbon and fluoropolymer producer, offers fluorinated aromatic and aliphatic building blocks. Solvay has its Solvay Fluor fluoroproducts unit and early this year moved responsibility for fluorointermediates to its Solvay Organics custom manufacturing business. Likewise, some of Rhodia's fluorination chemistry evolved from its expertise in triflic acid chemistry and in trifluoroacetic acid and derivatives.

Central Glass Co. in Japan has a position in HF, fluorinated gases, and triflic acid chemistry and supplies fluorinated compounds. It owns the fluorocompound custom synthesis and catalog supplier SynQuest Laboratories in the U.S. and has a stake in catalog supplier Apollo Scientific in the U.K. The company has made several fluorinated chiral intermediates on a large scale starting from building blocks such trifluoroacetaldehyde (fluoral) and trifluoroacetone (J. Fluorine Chem. 2006, 127, 8).

Central Glass researchers and Hoshi University collaborators also have synthesized a-monofluoromethyl- and a-difluoromethylbenzylamines through regioselective hydrogenolysis (J. Fluorine Chem. 2005, 126, 377). Research chemistry professor Jinbo Hu and coworkers at Shanghai Institute of Chemistry developed another route to these and other monofluoromethylamines. In what they believe is the first nucleophilic monofluoromethylation-that is, incorporating a CH2F group into an electrophile-they reacted fluoromethyl phenyl sulfone with a series of N-(tert-butanesulfinyl)imines and achieved very high stereoselectivities (Org. Lett. 2006, 8, 1693).

Asahi Glass Co. in Japan produces fluorinated polymers, gases, and solvents. It has a fine chemicals business in which fluorination is among its key technologies, and it makes fluorinated olefins, alcohols, ethers, ketones, halides, aromatics, and carboxylic acid derivatives as building blocks. It also owns 51% of F2 Chemicals, a U.K.-based firm specializing in selective direct fluorination.

Asahi Glass has developed a practical and safe process for making 3,5-bis(trifluoromethyl)phenyl Grignard reagent, which gives access to other 3,5-bis(trifluoromethyl)-substituted aromatics. "Those are key structures used in some blockbuster drugs right now," says Nick Kosarych, business manager for fluorochemicals at Asahi Glass Chemicals America.

Halocarbon Products Corp. has also added Grignard reactions to its capabilities in response to customer interest. "It allows us to make more sophisticated fluorinated building blocks from our existing products," Chief Executive Officer Peter A. Murin says. The company has been making fluorochemicals, including inert lubricants and anesthetics, for more than 50 years. It is a major producer of trifluoroethanol and related derivatives, as is Tosoh F-Tech in Japan.

Grignard reagents are already temperamental species, and reacting an organomagnesium halide with a fluorinated molecule, such as hexafluoroacetone, often in highly flammable solvents, makes for an even more unstable mix. "Because of our existing skill set in handling very reactive compounds, Grignard chemistry is a natural extension for us," says Barry Jones, Halocarbon's technical director. "Companies that can handle Grignard technology at large scale are fairly rare."

Despite efforts to generate new building blocks, many researchers bemoan the limited diversity of commercially available compounds. "Monofluorinated and trifluoromethylated aromatic or heteroaromatic rings are the most widespread," remarks Véronique Gouverneur, university lecturer in chemistry at Oxford University. "It's a very common structural motif in pharmaceutical chemistry, and so producers target that market, but there also may not be enough practical and synthetically useful methodologies out there for large-scale preparation of other structures."

Researchers point to the relative youth of organofluorine chemistry applications as one limiting factor. Until recently, requests for elaborated fluorinated molecules weren't very frequent, a factor that may have limited research into new building blocks. The increasing popularity of fluorinated drugs and agrochemicals, researchers hope, will boost the development and production of starting materials. Meanwhile, many labs create their own fluorinated structures.

Gouverneur's lab studies fluorination processes and has found, she says, that "the products are actually quite useful building blocks for further transformations." Her group has synthesized structurally diverse fluorinated compounds, including enantioenriched ones, through the electrophilic fluorodesilylation of allyl-, aryl-, vinyl-, and allenylmethylsilanes (Org. Biomol. Chem. 2006, 4, 26). These compounds include allylic fluorides with a variety of functionalities, fluorinated dienes, and more recently, propargylic fluorides from the fluorodesilylation of allenylsilanes.

"The allylsilanes are extremely versatile, and the corresponding allylic fluoride products are very important building blocks that have been underexplored because there were not that many valuable synthetic routes to them," she explains. She hopes to report soon on methods to place a fluorine, for example, on poorly activated positions. "We are trying to fill the gap and come up with synthetic routes to prepare highly functionalized fluorinated compounds with multiple stereogenic centers to understand how these structures might lead to drugs of improved potency."

In a different approach to generating diversity, Schlosser proposes regiochemically exhaustive synthesis. Hundreds, if not thousands, of compounds containing fluorine are available, he points out. "All that is needed to capitalize on such a bonanza are mild, universally applicable, and reliable methods for selective transformation, above all functionalization."

His group has published numerous examples of taking fluorinated core compounds, or "bulk chemicals," and then attaching functional groups at all the available positions. Because exactly how halogens will affect bioactivity can't be predicted, generating large families of related fluorinated building blocks should aid in designing active compounds, he explains.

For example, Schlosser and coworkers took 3-fluorophenol, an inexpensive compound with few known derivatives, and set out to attach a carboxyl group at each vacant site (Eur. J. Org. Chem. 2005, 2116). They did the same with 3-fluoropyridine, for which several carboxylic acid derivatives had been reported. The key to generating all four isomers of each starting molecule was site-selective metalation and the deployment of protecting and activating groups at neighboring positions.

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Schlosser has described the tools for these reactions in a review article (Angew. Chem. Int. Ed. 2005, 44, 376). His group has focused on fluorinated aromatic and heterocyclic substrates, which are converted into organometallic intermediates that can be combined with any number of electrophiles to make derivatives. They've applied the approach successfully to di- and trifluorophenols; monofluoroindoles; trifluoromethyl-substituted quinolines, pyrazoles, and pyridines; 2-fluoropyridine; and 2,4-difluoropyridine.

Floris P. J. T. Rutjes, chemistry professor at Radboud University in the Netherlands, has made fluorinated nitrogen-containing heterocycles through ring-closing metathesis (RCM). Synthetic methods for fluorine-containing, nonaromatic heterocycles are less well-established than for aromatics, despite their appearance in many bioactive compounds. Although RCM is an important synthetic tool, until recently it wasn't possible with terminal vinyl chlorides and fluorides.

"It wasn't until a more reactive second-generation Grubb's catalyst became available that it worked," Rutjes says. The first example using a vinyl fluoride was published by Richard C. D. Brown's group at the University of Southampton and a GlaxoSmithKline collaborator (Org. Lett. 2003, 5, 3403), followed soon after by Günter Haufe's lab at the University of Münster, in Germany, using fluoroacrylates (Tetrahedron Lett. 2004, 45, 57).

Rutjes and coworkers, in collaboration with Jörg Tiebes at Bayer CropScience, used RCM to synthesize a series of highly functionalized fluorinated piperidines, a popular ring structure in bioactive compounds (Eur. J. Org. Chem. 2006, 1166). As part of the work, they further functionalized a vinyl fluoride-containing cyclic amino acid derivative. "By changing the substituent on the nitrogen," Rutjes says, "you can make a rather modest library of biologically relevant compounds."

Introducing a fluorine or CF3 group directly onto a saturated ring system is very difficult, Rutjes explains, and there also may be functional groups that are not compatible with fluorination. With RCM, he says, "we also have some flexibility because we can alter the length of the chains we cyclize." To circumvent its reliance on commercially available starting materials, his group has developed a route to make its own fluorine-containing allylating reagents.

Thierry Billard, Bernard R. Langlois, and colleagues in the SERCOF Laboratory at Claude Bernard University in Lyon, France, have been creating CF3-containing carbo- and heterocycles through a variety of means, including RCM and Pauson-Khand and Heck reactions. Recently, they used β-fluoroalkylated enones to prepare cyclohexenones (Eur. J. Org. Chem. 2005, 3745) and, with Haufe and coworkers in Germany, as dienophiles in Diels-Alder cycloadditions (J. Org. Chem. 2006, 71, 2735).

"Diels-Alder reactions, and in a more general manner all the cyclization reactions, constitute an interesting and efficient way to easily access nonaromatic functionalized fluorinated structures," Billard says. He explores synthetic applications of β-fluoroalkylated α,β-unsaturated carbonyls, largely in cyclization reactions, in a recent review (Chem. Eur. J. 2006, 12, 974).

The advantages of such cyclization routes include obtaining cyclic structures for further syntheses, making fluorinated molecules without aggressive reagents, and the possibility that asymmetric syntheses can be more reasonably envisaged, he explains. Again, because the number of available nonaromatic fluorinated building blocks is limited, the researchers in Lyon devised an efficient and rapid method to make enones with various fluoroalkyl moieties (J. Org. Chem. 2001, 66, 4826).

Though synthetic chemists are familiar with building-block methods, fluorine can add a new twist. "The reactivity or selectivity of fluorinated molecules is often very different than their hydrogenated analogs because of the high-electron-withdrawing character of the fluorinated groups," Billard comments. Consequently, certain reactions don't occur as expected. But these differences are also what make working with fluorinated molecules interesting, he adds. "It's exciting to have to rediscover the chemistry by trying to 'forget' its background."

Another relatively new substituent, the pentafluorosulfanyl (SF5) group, is exciting researchers as well. More sterically demanding, more lipophilic, and more electronegative than a CF3 group, the SF5 group is stable on virtually any kind of benzene ring, the University of Florida's Dolbier says, unlike some trifluoromethyl variants. But for a long time, the problem was in putting SF5 groups onto organic structures.

DuPont scientists in the late 1960s used expensive silver difluoride to fluorinate diaryl disulfides to make pentafluorosulfanylbenzenes; although the process was later modified by others, yields generally remained low. About a decade ago, researchers at F2 Chemicals found a way to achieve the same conversion with elemental fluorine (Tetrahedron 2000, 56, 3399).

"We have scaled up the process to the pilot-plant scale and now can produce quite substantial quantities of these materials," says Martin P. Greenhall, R&D manager at F2 Chemicals. Miteni, a Mitsubishi subsidiary, that, with its parent, owns the rest of F2, has started marketing about 20 different pentafluorosulfanylbenzene derivatives.

In 2002, Dolbier came up with a way to add the SF5 group onto aliphatic compounds by using SF5Cl (Org. Lett. 2002, 4, 3013). Other techniques, including high-pressure autoclave and gas-phase photochemical processes, had been developed. "But these were techniques most organic chemists would generally not want to use," he says. "Our goal was to find a procedure that could be run on the benchtop by a pharmaceutical chemist." His group extended the approach to aromatics and more recently to functionalized and heterocyclic compounds.

Air Products & Chemicals, a manufacturer of SF4 and SF6, has developed a similar approach using SF5Br. Although the company hasn't commercialized the reagent or any derivatives yet, it has a research relationship with chemistry professor John T. Welch at the State University of New York, Albany. Together, they are exploring the downstream utility of the SF5 group in intermediates for pharmaceutical applications.

Welch's group, for example, has done side-by-side comparisons of SF5 and CF3 analogs of the herbicide treflan and drug compounds fluoxetine and fenfluramine. Many researchers and suppliers hope that SF5 chemistry will take off in the same way that the use of CF3 groups in bioactive compounds did. "There's really a lot of potential, and I think we have only scratched the surface," Welch says.

More studies of the biological effect of the SF5 group are anticipated to emerge as reagents and derivatives become available and interest is sparked. "Pharmaceutical companies need to be confident that these are available, then they'll start to put the SF5 substituents into their compounds, and when they find a good biologically active compound, it will open up a whole new field," Dolbier believes. He calls it the "substituent of the future."

Welch, likewise, is excited by the chemistry. "People have been working with carboxylic acids and amines for hundred of years," he says. "Just how many times do new substituents come along?"

MORE ON THIS STORY

Fabulous Fluorine

Having fluorine in life sciences molecules brings desirable benefits, but the trick is getting it in place and making sought-after building blocks

Constructing Life Sciences Compounds

Fluorinated building blocks are increasingly used as the basis of valuable active molecules

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