Stephen C. Stinson,C&EN Northeast News Bureau

Next week is Informex in New Orleans. At this one-of-a-kind exposition devoted solely to special-order production of chemicals, attendees from drug, agrochemical, and other fine chemicals consumer industries will visit with suppliers to learn how producers' capabilities fit with customers' needs.

SIGMA-ALDRIDGE FINE CHEMICALS PHOTO

But this year's Informex opens in a troubled atmosphere. According to Enrico T. Polastro of Arthur D. Little International, Brussels, the year 2000 brought warnings from fine chemicals producers about their earnings, announcements of divestments of fine chemicals businesses by larger firms, and the appearance of a depressed mood. Polastro, who is vice president and senior industry specialist for pharmaceuticals and fine chemicals, gave his views to the Fine Chemicals Conference in London this past November, a conference organized by Performance Chemicals magazine.

The fine chemicals industry, in which custom production occurs, was worth $50 billion in 1999, Polastro estimates. Of this, $35 billion, or 70%, was for the drug industry; $7.5 billion, or 15%, went for agricultural chemicals; and $2.5 billion, or 5% each, was for dyes, food and feed additives, and "other" production.

LOOKING AHEAD, Polastro believes the drug industry's share of fine chemicals will grow at 6% to 7% annually through 2004, while agricultural chemicals will grow only 1% per year in the period. He ascribes healthy growth for drug chemicals to the increased number of new chemical entities he expects to be introduced in the future, coupled with a continuing trend toward outsourcing. The low growth in agrochemicals is owing to past successes in crop seeds genetically modified for pest resistance. He estimates the whole class of fine chemicals will grow at 5% annually.

Looked at another way, $20 billion, or 40%, of fine chemicals production is captive, which means that the producers make the compounds for themselves, while $30 billion, or 60%, is merchant, which means it is sold to others. Merchant includes custom production. Polastro projects that the merchant market will grow at 5% per year through 2004 because of increased outsourcing, particularly for drug and agricultural chemicals.

Slicing up fine chemicals in yet another way, Polastro estimates that $20 billion, or 40%, is produced by Western Europe; $12.5 billion, or 25%, is made in North America; $7.5 billion, or 15%, comes from Japan; and $10 billion, or 20%, comes from the rest of the world. U.S. and Western European production is expected to grow 5% per year through 2004, fueled mainly by drug industry purchases. Japanese production will grow at 3% annually, he believes. Elsewhere in the world, a strong 7% annual growth from a smaller base will come from increases in India and China as their economies grow and their purchasing powers increase, leading to higher domestic consumption as well as exports.

Polastro estimates that 1999 custom chemicals production was $8.5 billion to $9.5 billion. Of this amount, $6 billion to $7 billion was for the drug industry, $1.5 billion for agrochemicals, and $1.1 billion for other entities. But beginning in 2000, outsourcing in fine chemicals fell out of bed. "Last year, the climate was gloomy," Polastro said, and the mood persists into this year as the U.S. economy seems headed into a slowdown.

One factor was the Y2K problem, the computer glitches that many predicted would arise as clocks turned over to the year 2000. Beginning in third-quarter 1999, companies stocked up on chemicals in anticipation. In the first quarter of 2000, companies found themselves overstocked as troubles failed to appear.

A second factor was the failure of an unusually high number of drug compounds in the pipeline, together with slower than expected growth for others. These shortfalls affected fine chemicals suppliers of the drug industry. Third, a number of large mergers among drug companies led to accumulation of production capacities at some surviving companies and delays in outsourcing decisions at others.

At the Fine Chemicals Conference, Henk Numan, business group director at DSM Fine Chemicals, Heerlen, the Netherlands, noted that, for drug companies, the driving forces have been the need for innovation, control of costs, and focusing on research, marketing, and distribution. These drivers have led to intensification of R&D at drug companies, a turning to outsourcing of production, and consolidation through mergers.

For the fine chemicals industry, these events at drug companies have led to expansion of chemical development capabilities, expansion of the "toolbox" of technologies, adaptation to custom production that services each step of drug development, the forming of partnerships with drug companies, and striving to reach some critical mass to sustain the increased level of business. The upshot of these efforts has been mergers to consolidate the fine chemicals industry as well.

"TEN YEARS AGO," Numan said in London, "the Top 10 pharma companies had a market share of 20%. Now, including the recently announced mergers and acquisitions, such as Glaxo [with] SmithKline and Pfizer [with] Warner Lambert, they have doubled it to 40%." And consolidation among customers has meant consolidation among the vendors. "Again," Numan went on, "comparing 10 years ago with today, the Top 10 fine chemicals companies had a market share of 10%. Now it's more than doubled to 25%."

DSM has been doing its share of mergers and acquisitions, picking up the ability to undertake custom manufacturing and to produce advanced intermediates by buying Andeno and Chemie Linz. The acquisition of Gist Brocades brought fermentation technology. And the acquisition of Catalytica has brought not only fine chemicals and drug production in the U.S., but also formulation of injectable and oral dosage forms.

Observers of the fine chemicals industry have suggested that DSM would divest the dosage form part of Catalytica, but in London Numan indicated a definite role for it. In particular, as the drug industry moves toward biopharmaceuticals, Numan said, DSM will join the biotechnological process development and scale-up ability of the newly formed DSM Biologics with the freeze-drying, sterile production, and dosage formulation strengths of Catalytica.

Detailing the growth of the biopharmaceuticals market, Numan pointed out that from 1998 to 1999 alone, while drug sales in general grew to $330 billion from $300 billion worldwide, biopharmaceuticals sales rose to $20 billion from $16 billion. The number of new biopharmaceuticals grew to seven from three, the number of such drugs in clinical trials to 538 from 450, and the number of products in preclinical trials to more than 900 from more than 700.

Also at the London conference, Alan Shaw, head of new business development for Clariant Life Science Molecules, Cadishead, England, detailed the consolidation in the drug and fine chemicals industries. Shaw also described his company's competitive position in responding to the new climate.

Shaw envisions particular value in the Lancaster Synthesis laboratory chemical catalog business that Clariant got with the acquisition of BTP. Lancaster offers 14,000 compounds, Shaw said, 5,000 of them proprietary. In Shaw's view, the catalog company furnishes tens to hundreds of milligrams, then tens to hundreds of grams of chemicals needed during discovery research and preclinical development. The catalog next blends seamlessly into tens to hundreds of kilograms made by Clariant's contract research organization and the ton quantities from contract manufacture. Thus the catalog business is a profitable mechanism to involve Clariant in all phases of drug development.

SCALING UP A repackaging station (top) is an integral part of Bayer's ZeTO pilot plant, which includes a 400-L reactor and distillate receivers (bottom).

THE COMPETITIVE EDGE of Bayer's basic and fine chemicals business group is ZeTO, which is the company's acronym for Zentral Technikum Organikum (pilot plant), according to plant head Klaus Jelich. At that pilot plant in Leverkusen, Germany, Jelich told the London conference, "we have a total of 340 employees, with a high percentage of chemists, engineers, and technical specialists."

Of the four buildings, two are warehouses and "the core part is the two buildings ZeTO I and ZeTO II with laboratories and offices at the front end of each building and with five production floors each." Among noteworthy facilities is a 400-L reactor with distillation receivers. The receiver vessels are piped back to the reactor so that it can also be used in liquid-liquid extraction. And then there is a repackaging station within a clean room unit so that the product can be handled in the open, either to take samples or to repackage according to customer specifications.

With important fine chemicals producers located in North America, Western Europe, and Japan, it's good business sense that the companies sell into one another's regions as well as to Asia. Jim Birnie, business manager for custom synthesis at Sumitomo Belgium in Brussels, related some of the issues in such trade to the London conference.

Two approaches that he described for selling into another country are the MacArthur style and the Napoleon style. Under MacArthur, the home office is the center of an "empire" and the local representative in the other country may not be able to tell customer prospects cogently what technology the company has. The Napoleon style, Birnie related, is like that emperor's delegation of authority to his marshals, who could campaign for extended periods in distant parts.

Asked which style is to be preferred, Birnie replied that the jury is still out. "It depends on the type of individual you're blessed with. Napoleon is the hardest for European or U.S. firms selling in Japan."

New forms of communication also make a difference, he said. "It's easier for a fine chemicals supplier to make a presentation if it visits the customer's website," he said, which allows the company to better tailor its proposal. E-mail allows same-day direct communication across many time zones, and with a mobile phone you can always reach someone for an urgent need. But, Birnie added, "some put on their answering machine."

Birnie noted a movement toward branding in the fine chemicals industry, which also can promote recognition in other countries. He referred to BASF's ChiPros brand of optically active intermediates and Lonza's slogan, "Leave it to Lonza."

In deciding how to enter a market in another country, Birnie said that costs spring from placing people and an organization in the other country. Once the people are there, costs accumulate. It is important to gauge projects carefully and take on new business, but avoid jumping into the wrong project. The fine chemicals producer can be hostage to accumulated costs. Or, as Birnie put it in London, "The longer you suck your teeth on a decision to plunge into a market, the odds shorten on your exiting."

Malcolm J. Braithwaite, chief executive of Exchem Organics, Great Oakley, England, told the London conference of a different lesson from the unsettling events in the life sciences industries of drugs and ag chemicals: "All this seems to be the result of major changes in the life sciences markets, particularly pharmaceuticals, and it leads us to ask, 'Is there life after life sciences?'"

He questions the "lemming-like" pursuit by hundreds of fine chemicals firms chasing fewer customers for ever decreasing volumes. Braithwaite's thesis is that there is plenty of business in the small-scale sectors of the industry.

Two sectors he singled out are electronic and reprographic chemicals. In electronic chemicals, there are the components of photoresist systems, such as diazonaphthoquinonesulfonic acid. This compound is a light-sensitive solubilizing agent in photoresists. In photocopying, he went on, there are complex synthetic organic molecules used as charge-generation and charge-transport materials. There is also crystal violet lactone, which functions in carbonless copy paper. And there are all of the ink pigments needed for printer processes.

Braithwaite ended by saying, "Of course there is 'life beyond life sciences,' and those companies that have the skill and dedication to stick with their fine chemicals businesses rather than sacrificing themselves and their employees on the altar of 'shareholder value' will survive and flourish."

After the presentation, however, he told C&EN: "I only hope that the audience was not too encouraged to dive into the markets discussed and create similar levels of overcapacity or cutthroat competitions as we see in the pharma and agro sectors."

Companies reacting to the new climate in producing chemicals to special order for their clients have responded in two ways. One way is to devise new chemical technologies for their own portfolios. The second way is to forge alliances with other firms to acquire rights to innovative technologies of those firms.

A case in point is Dow Chemical, whose business unit Dow Contract Manufacturing Services (CMS) has newly developed its own solutions to clients' production problems as well as made a recent alliance with Alchemia of Brisbane, Australia. In its own internal success story, Dow process chemists were confronted with a customer's need to make a few hundred kilograms of a p-fluorophenyl fluoromethylidene butylamine.

The customer's own chemists had devised a route that began with b-p-fluorophenethyl alcohol. This starting material was unavailable commercially and had to be made outside by custom synthesis. The customer's own process also called for elaborate further reactions of this compound in preparation for addition to ethyl tert-butyl malonate to assemble the four-carbon side chain. The mixed malonate ester was another intermediate that had to be made outside to special order.

The reaction scheme that process chemists at Dow CMS devised was to fabricate the four-carbon p-fluorophenylbutyl carbon skeleton all at once by Friedel-Crafts reaction of fluorobenzene with succinic anhydride. Both starting materials are commercially available at low cost. Dow chemists arrived at the needed ethyl tert-butyl mixed ester by esterifying a monocarboxylic acid with tert-butyl alcohol and then treating that ester in an active methylene condensation with diethyl carbonate.

The use of lower priced raw materials throughout reduced costs to $800 per kg of final product from $12,800 per kg for the customer's original route. The delivery time for the first 100 kg was eight to 12 months, compared to an estimated 18 to 22 months for the original process. The number of individual unit operations was reduced to 26 from 84. The multistep synthesis took up nine reactors compared with 22 previously. And the reactor use was lowered to 4,900 L-hours of capacity per kg of final product.

In its new alliance with Alchemia, Dow CMS gains access to the Australian firm's proprietary carbohydrate synthesis technology. The first two projects for the new partners are oligosaccharides to treat rejection of transplants from animals and to prevent an occasional antibiotic-induced intestinal disorder that is potentially fatal.

As Dow CMS scientist Mike Fazio puts it, "This alliance combines the strengths of both organizations to meet a need in the marketplace. Working with Alchemia in the area of carbohydrate chemistry, Dow will expand its ... capabilities portfolio and allow it to serve the needs of a growing industry. The background in carbohydrate chemistry provided by Alchemia coupled with Dow CMS's pharmaceutical manufacturing capabilities will provide the customer with material and assurance of supply needed for successful product development and commercialization."

ALCHEMIA'S TECHNOLOGY is solid-phase synthesis. The company has developed specific protection and deprotection tactics for each of the five hydroxyl or amino group positions on a pyranose. In particular, the company has developed a derivative of dimedone that can bind to and protect an amino group and/or link a sugar molecule to a resin. The dimedone is cleavable with hydrazine.

Rejection of pig tissue transplanted into humans is largely caused by a disaccharide of galactose, called diGal [Gal(13)Gal], on organ cell surfaces. The joint project aims to make large amounts of diGal, immobilize diGal on the surface of a column packing, and pass the blood of transplant patients through the column to tie up antibodies to diGal.

The antibiotic-induced colitis being addressed by another project is caused by a toxin of the bacteria Clostridium difficile. Certain antibiotics in some patients wipe out many bacterial species that live in the human gut. This can pave the way for overgrowth of C. difficile, which normally can't compete.

The C-terminal third of the toxin chain binds to oligosaccharides on human gut cell surfaces. The N-terminal third exerts the toxic effect of damage to gut cells, making them unable to control fluid inflow and outflow and accumulation of deposits of blood, mucus, and other fluid.

The toxin binds to a trisaccharide of galactose and N-acetylglucosamine [Gal(13)Gal(14)GlcNAc]. By making large amounts of the trisaccharide and adding it to intravenous feeding solutions, the trisaccharide may bind to toxin molecules locally, preventing them from binding to cells.

Yet another alliance is that between Aldrich Chemical and Rieke Metals, Lincoln, Neb. Rieke Metals was founded by organic chemistry professor Reuben D. Rieke of the University of Nebraska, who is company president. Rieke discovered that treating metal salts with a reducing agent of naphthalene treated with lithium, sodium, or potassium in ether produced those metals in a finely divided, extremely reactive form. Aldrich sells Rieke metals, including magnesium in tetrahydrofuran. Aldrich recently opened a new facility in Sheboygan, Wis., for handling and producing such air-sensitive materials.

Recently, Rieke has found that magnesium forms Grignard reagents at -78 °C with substrates that have functional groups that usually are incompatible with Grignard reagents [J. Org. Chem., 65, 5428 (2000)]. Examples are p-carbo-tert-butoxyphenyl-, p-cyanophenyl-, and p-chlorophenylmagnesium bromides. Rieke demonstrates reactions of such Grignard reagents with benzaldehyde, benzoyl chloride, and allyl iodide.

ONE MORE ALLIANCE is that between Cambrex and Synthon Chirogenics, Monmouth, N.J. Synthon was founded by organic chemistry professor Rawle I. Hollingsworth of Michigan State University. Hollingsworth, who is the company's chief scientific officer, invented a process to convert lactose to (S)-3-hydroxybutanolactone and L-arabinose to the (R)-enantiomer.

He has since parlayed those two compounds into a few dozen optically active C₃ to C₅ intermediates. The alliance calls for Cambrex to buy a $3 million minority share in Synthon, produce certain Synthon intermediates on a large scale, and offer Synthon technology for custom manufacture.

In addition, Cambrex and Synthon will synthesize combinatorial libraries of compounds based on a threonine aldolase developed by Cambrex and aldehydes made by Synthon. The aldolase catalyzes such reactions as that of benzaldehyde with glycine to form phenylserine.

The raw materials are inexpensive and the initial process involves only aqueous sodium hydroxide and hydrogen peroxide. Lactose is a by-product of cheese making and arabinose is recovered from sugar beet processing waste.

Most recently, Hollingsworth has used the (R)- and (S)-lactones to make single-isomer 3-amino- and 3-hydroxypyrrolidines, 4-hydroxypyrrolidinones, and 5-hydroxymethyloxazolidinones. He described these advances to the ChiraSource 2000 symposium in Lisbon, Portugal, in October 2000.

Some conversions that he described in Lisbon use such costly and difficult reagents as lithium aluminum hydride (LAH), diborane, and methanesulfonyl chloride. But Synthon process chemists tell C&EN that they are used to adapting chemistry from Michigan State to commercial application.

For example, treatment of (S)-3-hydroxybutanolactone with LAH gives 1,2,4-butanetriol, which Hollingsworth converts to the methanesulfonate triester. Reaction of that ester with an amine such as methylamine displaces all the ester groups with inversion of configuration to give (R)-N-methyl-5-methylaminopyrrolidine.

In another route, ammonium hydroxide converts (S)-lactone to (S)-3,4-dihydroxybutanoamide, which Hollingsworth protects as the 5-triphenylmethyl (trityl) ether. That compound undergoes a Hoffmann rearrangement with sodium hypochlorite. In a usual Hoffmann rearrangement, the intermediate isocyanate hydrolyzes to give an amine. In this case, however, the isocyanate snakes back on the hydroxyl group and closes the ring to form (S)-5-trityloxymethyl-1,3-oxazolidin-2-one.

Finally, reaction of (S)-lactone with hydrobromic and acetic acids yields (S)-3-acetoxy-4-bromobutanoic acid. Hollingsworth treats the methyl ester of that acid with an amine such as methylamine to form (S)-4-hydroxy-N-methyl-2-pyrrolidinone. That lactam can be reduced with diborane to (S)-3-hydroxy-N-methylpyrrolidine.

Daicel Chemical Industries of Tokyo has its own academic alliance with the research group of applied chemistry professor Yasutaka Ishii at Kansai University in Osaka, Japan. Ishii has developed a number of reactions for Daicel based on using N-hydroxyphthalimide (NHPI) as a catalyst.

Takeshi Matsumoto, manager of marketing and development at Daicel's biochemical products division explains, "We would like to supply the products produced by the technology using the catalyst. We would also like to offer contract manufacturing services using the technology. We have many process patents using the catalyst."

The most recent such reactions have been low-temperature air oxidations of secondary alcohols to ketones [J. Org. Chem., 65, 6502 (2000)] and low-temperature nitrations of alkanes with nitrogen dioxide and air [Angew. Chem. Int. Ed., 40, 222 (2001)]. In the alcohol oxidation, Ishii stirs ethyl acetate solutions of alcohols with catalytic amounts of NHPI, cobalt(II) acetate, and a substituted benzoic acid in sealed vessels at room temperature under air. It is easy to imagine extension to a continuous process in which air is blown through a solution in a high-boiling solvent and the ketone product separated as the most volatile component. Under Ishii's conditions, -phenethyl alcohol gives 98% yield of acetophenone, cyclohexanol gives 83% of cyclohexanone, and 2-octanol gives 75% of 2-octanone.

IN THE ALKANE NITRATION, Ishii heats a mixture of alkane, nitrogen dioxide, and NHPI with access to the air under reflux or at 70 °C. Again, one can imagine blowing alkane vapor, nitrogen dioxide, and oxygen continuously through an NHPI solution, fractionating the organic products, and recycling unreacted alkane.

The products are the nitroalkane, alkyl nitrate, and alcohol. Thus cyclohexane yields 70% of nitrocyclohexane, 7% of cyclohexyl nitrate, and 5% of cyclohexanol. The yields of nitro compounds alone from hexane are 2% of 1-nitrohexane, 29% of 2-nitrohexane, and 24% of 3-nitrohexane. Isobutane gives 46% yield of 2-methyl-2-nitropropane only.

By contrast, the classical vapor phase nitration invented by organic chemistry professor Henry B. Hass of Purdue University goes in low yields at 420 °C and gives a complex mixture of products resulting from fragmentation of carbon skeletons. For example, Hass's nitration of propane gives 21% of a mixture of 1- and 2-nitropropanes, nitroethane, and nitromethane.

Elsewhere in academic-industrial partnerships, Buchler of Brunswick, Germany, works with organic chemistry professor H. Martin R. Hoffmann at the University of Hanover to make derivatives of quinuclidine (1-azabicyclo[2.2.2]octane) available from alkaloids in cinchona bark. Single-isomer derivatives of quinuclidine comprise parts of the structures of dozens of drugs and drug candidates. Such derivatives are also useful as enantioselective phase-transfer catalysts and as ligands for catalysts for asymmetric synthesis.

Cinchona alkaloids have a long tradition at the company, founded as Hermann Buchler's Quinine Factory in 1858. Buchler today has relationships with plantations in the Democratic Republic of the Congo, Burundi, Tanzania, and Guatemala to ensure long-term supplies of cinchona bark.

THE CINCHONA ALKALOIDS all have syn-5-vinyl and 2-carbinol substituents on the quinuclidine nucleus. Quinine and cinchonidine both have endo-2-carbinol groups, while quinidine and cinchonine have exo-2-carbinol groups. All four alkaloids are linked through the carbinol carbon to quinoline nuclei. Hoffmann has found a way to cleave the quinoline without destroying the quinuclidine portion.

His method is to treat the alkaloid with LAH and tetramethylethylenediamine, followed by stirring in air. Quinine or cinchonidine yields endo-2-hydroxymethyl-syn-5-vinylquinuclidine, which Hoffmann has trade named Quincorine. Quinidine or cinchonine yields the exo-2-hydroxymethyl derivative, which Hoffmann has trade named Quincoridine.

A partnership between two Canadian companies has resulted in acquisition of a new compound by BioVectra of Charlottetown, Prince Edward Island, as that company repositions itself toward custom manufacture. BioVectra will process kainic acid (2-carboxy-3-carboxymethyl-4-propenylpyrrolidine) from Ocean Produce International of Shelbourne, Nova Scotia.

Kainic acid is a research tool in neurology that has recently been in short supply (C&EN, March 6, 2000, page 31). Ocean Produce is farming an alga mutant that produces relatively large amounts of kainic acid. Wayne Nowicki, business development director at BioVectra, says his firm has 250 g of the acid so far and will make up dilute solutions in vials containing assayed amounts of the acid.

BioVectra was founded in 1970 mainly to develop chemistry for clinical diagnostic kits. In the present repositioning, the company will make proteins to special order from bacterial or mammalian cell cultures and develop purification and refolding methods.

Another transfer of technology between companies is the 1999 acquisition by Natural Pharmaceuticals, Beverly, Mass., of the oncology division of Hauser, Boulder, Colo. Included were tens of kilograms of the anticancer drug paclitaxel, nurseries of paclitaxel-producing yew trees, and patents covering interconversion of taxane derivatives. Natural Pharmaceuticals is thus able to perform these interconversions to special order for custom clients.

One such interconversion is replacement of an acetamido group on a taxane side chain. After protection of hydroxyl groups as triethylsilyl ethers, the compound is treated with bis(cyclopentadienyl)chlorozirconium hydride, which converts the acetamido to an acetylimine group. Hydrochloric acid hydrolyzes the imine to the free amine, which is reacylated with benzoyl chloride to give paclitaxel.

Elsewhere, SNPE of Paris continues to bolster its offerings of phosgene-based technology for custom production. SNPE acquired Multiple Peptide Systems of San Diego in 1999, whose own peptide synthesis technology joins nicely with SNPE's phosgene. For example, phosgene can serve as a condensing agent to form bonds between acyl and amino groups. Phosgene also is a raw material for such amino protecting groups as benzyloxycarbonyl. And phosgene reacts with amino acids to form N-carboxy anhydrides, which are protected, activated peptide synthesis intermediates.

Hickson DanChem of Danville, Va., has both acquired technology to make surfactants from Shell and formed a partnership with PolyCarbon Industries, Leominster, Mass. The company licensed the Neodox trade name from Shell and introduced two new surfactants in that line: ethoxylated nonylphenol and ethoxylated tridecyl alcohol.

The oxidation technology uses a proprietary catalyst for air oxidation of the terminal hydroxyl group of ethoxylated surfactants to a carboxyl group. The resulting carboxylate surfactants can be made to special order for formulators of personal care products such as bar soaps and shampoos. The alliance with PolyCarbon Industries lets both companies offer the laboratory-scale production of PolyCarbon with the commercial-scale production of Hickson.

General Electric is another firm that is evaluating new technology and its application to custom chemicals production. GE is in the process of deciding what to do with the chemical properties to be acquired by its merger with Honeywell, which came by these properties from an earlier merger with AlliedSignal. Meanwhile, GE Plastics has begun offering organic intermediates based on production of its monomers and polymers. New offerings include N-methylphthalimide and its 4-nitro derivative, as well as 4,4'-isopropylidenebis(4-phenoxyphthalic) anhydride.

In addition to those companies that acquire chemical technology in partnerships, other firms work to expand their own portfolios. For example, research fellow Q. B. (Rinus) Broxterman of DSM Fine Chemicals described the firm's new amino acid protecting group technology to the ChiraSource conference. Broxterman demonstrated use of the sulfamate group to mediate synthesis of the dipeptide L-phenylalanyl-L-phenylalanine.

BROXTERMAN BEGINS by treating phenylalanine methyl ester with chlorosulfonic acid and triethylamine. This reaction applies the sulfamate -NHSO₃H group. The next step is saponification of the ester and generation of the freeze-dried carboxylic sulfamic diacid for storing or shipping.

He activates the carboxyl group by reaction with pivaloyl chloride. He is uncertain about the structure of the activated intermediate, which may be either a mixed pivalic-phenylalanine anhydride or the 4-benzyl-1,2,3-oxathiazolidin-5-one S,S-dioxide. Addition of a second mole of phenylalanine methyl ester to the activated intermediate forms the peptide bond. Treatment with hydrogen chloride in dioxane removes the sulfamate group from the dipeptide.

Success with chlorosulfonic acid is noteworthy because the compound costs only 50 cents per kg. And removal of the sulfamate group is by simple acidification without the need for hydrolysis. The one disappointment in the project is the inability to surpass existing technology for coupling phenylalanine methyl ester with aspartic acid to make the synthetic sweetener aspartame. However, a pleasant bonus result is the discovery that chlorosulfonic acid mediates quantitative methyl esterification of such amino acids as phenylalanine, tyrosine, and p-hydroxyphenylglycine at 70 to 75 °C over 20 to 30 minutes.

Two companies, Cytec Canada, Niagara Falls, Ontario, and GFS Chemicals, Powell, Ohio, are working to deepen penetration of their classes of compounds into fine chemicals production. The expertise of Cytec is in trialkyl phosphines; that of GFS is in perchlorate salts.

Mike Chernishenko, who is product manager at Cytec's phosphine technical center, tells C&EN that compounds such as tricyclopentylphosphine are finding uses as catalyst ligands and synthetic reagents in preference to triphenylphosphine. This is because most trialkylphosphines are liquids, which can be dispensed by metering, unlike the solid triphenylphosphine. In addition, their coproducts in organic reactions are sometimes phosphine oxides, which in the trialkyl case are water soluble.

MOLECULAR WEIGHTS of the alkylphosphines are often lower, which means more moles of phosphorus per kilogram of phosphine. Chernishenko also points to the multiton production rates of Cytec, together with the company's expertise in handling and shipping the materials. And for those who do not want to handle phosphines, Cytec can use them in custom production.

For his part, John R. Long, director of technology at GFS Chemicals, is working to spread the word that anhydrous lithium perchlorate in diethyl ether is a desirable solvent for enhancing rates of certain organic reactions. So soluble is lithium perchlorate that up to 47% solutions are possible in diethyl ether.

Such usage runs counter to most chemists' sense that perchlorates and organics make a hazardous combination. But Long cites work of organic chemistry professor Paul A. Grieco, first at Indiana University, Bloomington, and now at Montana State University, to demonstrate rate enhancements of Diels-Alder, Michael addition, and Claisen rearrangement reactions.

As for safety, GFS has commissioned calorimetry by an outside laboratory. Heating such solutions in sealed vessels leads to an exotherm beginning at 160 °C, which is controllable to 220 °C, at which point it goes out of control. Because most reactions will be carried out below 100 °C, the solvent system is safe, Long asserts. GFS produces lithium perchlorate in ton lots, and for those who do not want to handle ether solutions, the company will use them to carry out reactions for custom production.

Yet another firm, Ychem International, Cupertino, Calif., hopes to make a mark in the fine chemicals industry by developing its own kits of solvents and resolving agents to evaluate resolution of racemic mixtures by diastereoisomeric crystallizations. Company president Niteen A. Vaidya described his company's technology and offerings to the ChiraSource conference.

For now, the company offers kits at $499 each to test resolutions of racemic acids and bases. For the future, the firm will work with instrument companies to develop an automated workstation consisting of an automated weighing station, solution-phase synthesizer, liquid chromatograph, and chiral detector. The company has applied for patents on automated evaluation of resolving agents and solvents.

The kit has six bases, such as (–)--phenethylamine, and six acids, such as (–)-mandelic acid. Each acid and base is dissolved in eight solvents, such as methanol or 80% aqueous methanol, for a total of 48 vials. Future kits will include phthalic or succinic anhydrides to derivatize alcohols, 4-sulfophenylhydrazine or 4-(4-carboxyphenyl) semicarbazide to derivatize ketones, or formaldehyde to protect amino acid amino groups.

New technology for production of custom chemicals also results from independent academic research. The university chemists involved may not be in any particular industrial partnerships, but the chemistry they develop is available for licensing.

For example, organic chemistry professor Roger A. Sheldon of Delft University of Technology, in the Netherlands, has worked out a practical application of aldolase enzyme technology to large-scale production [J. Org. Chem., 65, 6940 (2000)]. There are four aldolases that depend on dihydroxyacetone phosphate (DHAP) as a substrate to produce the diastereoisomeric ketoses fructose, fuculose, rhamnulose, and tagatose. The use of these aldolases to make nonnatural sugars using various aldehydes has been worked out by chemistry professor Chi-Huey Wong at Scripps Research Institute.

But DHAP is an absolute requirement, and that intermediate is costly. Organic chemistry professor Wolf-Dieter Fessner at the Technical University of Darmstadt, in Germany, has combined an enzyme that makes DHAP with the aldolase, but it has fallen to Sheldon to reduce the whole method to a one-pot procedure needing only glycerol and the aldehyde substrate.

SHELDON'S METHOD begins with phytase to mediate phosphorylation of glycerol by pyrophosphate to racemic glycerol phosphate. The next enzyme in the pot, glycerol phosphate oxidase (GPO), is specific for L-glycerol-3-phosphate. Glycerol and pyrophosphate are inexpensive, however, so Sheldon deems it cost effective to waste the other isomer in the racemate. GPO mediates oxidation by air to DHAP with cogeneration of hydrogen peroxide. Sheldon eliminates buildup of hydrogen peroxide by catalase, which disproportionates that compound to oxygen and water. D-Fructose-1,6-diphosphate aldolase accepts its natural substrate DHAP and the nonnatural butyraldehyde for the carbon-carbon bond-forming step. Finally, phytase acts once again to dephosphorylate the product.

Another enzyme project, not nearly so far along but with great potential, is the 2,3-aminomutase discovered in the mushroom Cortinarius violaceus by organic chemistry professor Wolfgang Steglich at Ludwig Maximilian University in Munich [Angew. Chem. Int. Ed., 39, 2754 (2000)]. This enzyme catalyzes rearrangement of its natural substrate (S)-phenylalanine to (R)--phenylalanine. (The change from S to R is owing to the nomenclature convention and not to change of configuration.)

Natural and nonnatural -amino acids are important for making certain drugs, so an enzymatic route to those compounds would be a valuable adjunct to asymmetric synthesis. Earlier progress on 2,3-aminomutases has come from the work of bioorganic chemistry professor Heinz G. Floss at the University of Washington.

Just as Delft's Sheldon has brought aldolases within reach of commercial production of fine chemicals, organic chemistry professor Martin Wills of the University of Warwick, in Coventry, England, has demonstrated a potentially industrially significant asymmetric hydroformylation with a catalyst ligand of his own invention [Angew. Chem. Int. Ed., 39, 4106 (2000)]. In particular, Wills has succeeded in hydroformylating vinyl acetate. The catalyst is rhodium chelated by a bis(diazaphospholidine) in which the chirality is at phosphorus.

The overall yield is 90% of a mixture that is 94.5% O-acetyllactaldehyde and 5.5% -acetoxypropionaldehyde. The lactaldehyde is formed in 89% enantiomeric excess and, like the lactones of Synthon Chiragenics, could become the source of a whole tree of optically active intermediates for synthesis.

THREE RESEARCH GROUPS report progress in regioselective reaction of one of two identically placed functional groups in a molecule. Workers at Scripps Research Institute have succeeded in making polyethylene glycol ethers of defined molecular weights capped at one end. Chemists at the University of Waterloo in Ontario convert 1,-diols selectively to bromo alcohols. And investigators at Oklahoma State University hydrolyze one out of two carboxylate groups in a symmetrical structure.

Ordinarily, such selective reactions are carried out by enzymes. Often an advantage in such a case is that in prochiral substrates the product is a single isomer resulting from the enantioselectivity of the enzyme. But an enzyme offers no guarantee in advance of enantioselectivity or yield.

Chemistry professor Kim D. Janda of Scripps begins with commercially available 2-benzyloxyethanol, which he treats first with potassium hydride and then with a measured amount of ethylene oxide [J. Org. Chem., 65, 5843 (2000)]. The product is polyethylene glycol of molecular weight 1,000, 2,000, or 4,500, capped on only one end with a benzyl group. This product serves as a springboard for other interconversions. For example, reaction with tert-butyldimethylsilyl (TBDMS) chloride puts a TBDMS group on the other hydroxyl group. Hydrogenation of that product cleaves the benzyl group, leaving only the TBDMS group on the other end.

Organic chemistry professor J. Michael Chong of Waterloo finds that almost all of the literature methods for making bromo alcohols from diols suffer from poor yields or lack of selectivity or both. His present method is stirring a mixture of diol in toluene with 48% hydrobromic acid under reflux [J. Org. Chem., 65, 5837 (2000)]. From 1,8-octanediol, for example, he gets about 90% yield of 8-bromo-1-octanol with only 2% of dibromide and 1% of unreacted diol. He suggests that the bromo alcohol forms micellelike structures in the toluene in which polar hydroxyl groups are pointed into the center and thus kept away from exposure to the aqueous brominating agent.

A SIMILAR TWO-PHASE mechanism that protects his saponification products from further reaction is likewise suggested by organic chemistry professor Satomi Niwayama of Oklahoma State. He dissolves the diester in THF and adds that to dilute sodium hydroxide and stirs at 0 °C. Yields are high, and epoxide groups go unmolested. For example, the monoepoxide of the Diels-Alder product of cyclopentadiene and dimethyl or diethyl acetylenedicarboxylate yields monoester in greater than 99% yield.

Niwayama proposes that at the low temperature the reaction mixture is a two-phase system. The already reacted carboxylate anion ties up the unreacted ester grouping in the less polar phase in such a way as to protect it from action of hydroxide ions.

Four research groups report progress in metal-mediated syntheses. These results may lead to improvements in the use of metals or to reactions that avoid metals entirely. Issues for use of metal include toxic residues in organic products and the treatment of metal wastes.

For example, researchers at the National Tsing Hua University in Hsinchu, Taiwan, have worked out a nickel-zinc replacement for organolithium or organomagnesium reagents. In a similar vein, chemists at Tulane University have devised Grignard-like reactions with magnesium or tin that proceed in water solution in the presence of air. Workers at the Institute of Organic Chemistry & Synthesis in Rosario, Argentina, report a method to treat tin wastes that result from such reactions. And a group at California Institute of Technology has run the first asymmetric 1,3-dipolar addition with an all-organic nonmetal catalyst.

Organic chemistry professor Chien-Hong Cheng in Taiwan uses a nickel(II) chelate of tetraphenylethylenediphosphine to catalyze coupling of aldehydes and aryl bromides by zinc [Org. Lett., 2, 2295 (2000)]. He demonstrates the method with p-bromoanisole and benzaldehyde in THF, which yield 91% of p-methoxydiphenylcarbinol.

TIN REAGENTS in water and air are the invention of organic chemistry professor Chao-Jun Li at Tulane to replace organolithium and organomagnesium reagents [J. Am. Chem. Soc., 122, 9538 (2000)]. In one example, a rhodium(I) salt catalyzes reaction of trimethylphenylstannane with p-formylbenzonitrile to give 92% of p-cyanodiphenylcarbinol.

To dispose of trimethyltin oxide or unreacted phenyl reagent, organic chemis-try professor Oreste A. Mascaretti in Argentina heats these with mixed concentrated nitric and hydrochloric acids at 85 °C for an hour [J. Org. Chem., 65, 9220 (2000)]. He next adds thioacetamide, which precipitates tin(IV) sulfide. This treatment both knocks the tin out of solution and destroys toxic trisubstituted tin derivatives.

Organic chemistry professor David W. C. MacMillan at Caltech makes the all-organic nonmetal catalyst for his asymmetric 1,3-dipolar addition by reaction of (S)-phenylalanine methyl ester, methylamine, and acetone [J. Am. Chem. Soc., 122, 9874 (2000)]. The product is (S)-4-benzyl-1,2,2-trimethylimidazolidin-5-one. This compound catalyzes reaction of crotonaldehyde with benzylidinebenzylamine oxide to give an isoxazolidine in 70% yield and 93% enantiomeric excess.

All these developments are examples of the creative scientific and technological thinking that ultimately will underpin future growth in the custom chemicals sector. But the current uncertain economic climate may mean that realization of that potential will not be achieved in the immediate future.

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MEETINGS

Expositions And Symposia Highlight Custom Chemicals

Jan. 30–Feb. 2, Informex. New Orleans. Contact Synthetic Organic Chemical Manufacturers Association, care of Laser Registration, 1200 G St., N.W., Washington, D.C. 20005; phone (514) 847-0512, fax (514) 289-9844.

May 14–15, Chiral USA 2001. Boston. Contact Scientific Update, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, U.K.; phone 44 1435 873062, fax 44 1435 872734; e-mail: sciup@scientificupdate.co.uk.

May 16–17, Outsource USA '01, Boston. Contact Scientific Update.

June 20–21, ChemSpec Europe 2001. Amsterdam. For the exposition, contact DMG World Media, 2 Queensway, Redhill, Surrey RH1 1QS, U.K.; phone 44 1737 768611, fax 44 1737 855469; jayminamin@uk.dmgworldmedia.com. For the symposium, contact the British Association for Chemical Specialities, The Gatehouse, White Cross, Lancaster LA1 4XQ, U.K.; phone 44 1524 849606, fax 44 1524 849194; e-mail: enquiries@bacsnet.org.

Oct. 8–10, Conference on Pharmaceutical Ingredients. London. For both the conferences and exposition, contact Miller Freeman, Industrieweg 54, 3606 AS Maarssen, the Netherlands; phone 31 346 559444, fax 31 346 573811; e-mail: NKlein@unmf.com.

Nov. 12–14, ChiraSource 2001. Philadelphia. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; phone (215) 628-4447, fax (215) 628-2267; e-mail: cnf@catalystgrp.com.

Nov. 19–20, Fine Chemicals Conference 2001. London. Contact Folio Consultants, Braeside, High St., Oxshott, Surrey KT22 OJP, U.K.; phone 44 1372 841010, fax 44 1372 841012; e-mail: paulfolio@aol.com.

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