COVER STORY
July 9, 2001
Volume 79, Number 28
CENEAR 79 28 p.65-84
ISSN 0009-2347
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FINE CHEMICALS
Last year saw disappointing growth in both pharmaceutical and agricultural fine chemicals; firms and academics continue to create new technology

STEPHEN C. STINSON, C&EN NORTHEAST NEWS BUREAU

The manufacturer of fine chemicals--pure substances bought and sold on the basis of their chemical identity--will always be a given: drug and agricultural chemical companies won't survive without them. But recently the market performance of the fine chemicals sector hasn't been what it once was.

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MADE TO SPEC Strem chemist Dave Geissler fills out a batch record for cisplatin, an anticancer drug, manufactured in one of Strem's new cGMP kilo-lab suites in Newburyport, Mass.
PHOTO BY GREG NIKAS PHOTOGRAPHY
"Growth in the fine chemicals industry during 2000 was quite disappointing--about 2%," Enrico T. Polastro tells C&EN. "Other observers have spoken of a turnaround in 2001," he says, "but first-quarter results do not support that view."

Polastro, who is vice president and senior industry specialist for pharmaceuticals and fine chemicals at Arthur D. Little International in Brussels, adds that growth in agricultural chemicals has been flat and that growth in pharmaceutical fine chemicals has been disappointing because of lower production volumes, problems with individual drugs, and price erosion.

"Custom synthesis stagnated, if it did not actually decline," Polastro says. "Some drugs failed to meet sales expectations. Others were withdrawn. This spelled very bad news for some contract manufacturers." In addition, merger activities in the drug industry led to accumulation of capacity, leading to what Polastro quips as "insourcing." Price pressures lowered profits as a percent of sales to 10% from 13%, he estimates. And decreased capacity use lowered returns on capital invested to 12% from 17%.

Polastro's impressions indicate that worldwide fine chemicals sales in 2001 might reach $52 billion--divided among drug intermediates, $37 billion; ag chemicals, $7.5 billion; and dyes, food and feed additives, and other, $2.5 billion each. Of the total, custom chemicals, which are fine chemicals produced to special order, account for as little as $8 billion.

By contrast, Polastro sees great prosperity in the biopharmaceutical area. Worldwide demand grew to $500 million in 2000 from $300 million in 1997, he says. "There are capacity constraints in biopharmaceuticals," he says. "It's a good business to be in." Indeed, he cites the purchase of the Covance biotechnology services unit by the Diosynth division of Akzo Nobel (C&EN, April 30, page 12) and that of Bio Science Contract Production by Cambrex (C&EN, May 7, page 17) as evidence that others think so also.

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BLASER BILTZ
ALTHOUGH CURRENT market conditions have put a crimp in outsourcing of fine chemicals production, outsourcing still goes on. Rob Bryant outlined the current state of affairs--which he describes as a crisis--to the Outsource 2001 conference put on by Scientific Update of Mayfield, England, in Boston in May.

Bryant, who is the proprietor of Brychem Business Consulting in Orpington, England, put it bluntly: "There is a crisis of confidence in pharmaceutical fine chemicals. Contracts have been canceled and relationships broken off. There are no partnerships in this industry, only master-slave relationships. There are no partnerships between lions and lambs."

He ascribed a current juncture in pharmaceutical fine chemicals to a shortfall in the drug pipeline and "merger mania" among drug firms. That has led, he said, to a domino-effect profit decline among fine chemicals producers, which have responded with their own merger mania. Mergers among drug firms have led to rupturing of relationships as merged firms have lost momentum in resuming developments of compounds of each company prior to mergers. Bryant further pointed to overinvestment in fine chemicals capacity owing to "cGMP mania" (referring to the Food & Drug Administration's continually evolving production regulations called current good manufacturing practices).

Yet another casualty Bryant sees is process development. Processes are increasingly locked in at early stages, he pointed out, as process development ceases prematurely.

Consultants advised large chemical companies to get into fine chemicals as a means of achieving higher profitability, Bryant said. Yet the fine chemicals businesses of the large chemical companies have been so small as not to affect the balance sheet. The result, Bryant said, has been a disaster for all concerned.

Meanwhile, the threat of Asian fine chemicals producers has been looming over producers in Europe and North America. "The scale of their internal drug markets has driven the rise of the Indian and Chinese pharmaceutical fine chemicals industries," Bryant said. "Chemists there are well educated and well paid. What keeps them out of Western markets is the perception in the West that they are [not up to standards]. Regulatory and economic trade barriers will only delay the inevitable and weaken those firms sheltering behind trade barriers." Of the future, he said, "Asian fine chemicals producers will make all active pharmaceutical ingredients except the newest ones."

Also at Outsource 2001, John K. Thottathil of Bristol-Myers Squibb, gave the drugmaker's perspective on issues that affect fine chemicals suppliers. The number of drugs approved that are new chemical entities has remained static at about 35 per year, he said. But the number of investigational new drugs entering clinical trials each year has been growing steadily over the years from about 300 in 1987 to more than 500 today. "The reason is that companies are killing bad compounds earlier," he said.

A SECOND INSIGHT that Thottathil gave is the number of compounds that a drug company must juggle in a steady state. The time period from preclinical work to approval and marketing is about eight years. In preclinical research, there may be 30 compounds introduced for study in year one. In year two, there are only 18 compounds left entering clinical trials. As clinical trials become larger in scale and more complex, in year three there are 12 compounds left; in year four there are 10; in year five there are eight; in year six there are six; in year seven there are four; and of the original 30 compounds, three may be launched in year eight.

But this static model of dwindling numbers of one year's compounds masks the effect of the company's entering 30 compounds each year into the pipeline. Thottathil shows that at any one time, a drug company actually juggles a portfolio of 91 compounds in various years of their development. This situation affects the efforts that the drug company must make to secure different amounts of drugs and intermediates.

Reaction to the fine chemicals business downturn is mixed. One firm that would seem to be taking Bryant's advice is Eastman Chemical, Kingsport, Tenn. That company announced plans earlier to sell its fine chemicals business (C&EN, Sept. 25, 2000, page 13). But Eastman later said that it could not come to terms with a buyer for the whole business, and that it would continue trying to sell its Peboc division in Llangefni, Wales, and drugmaking plant in Hong Kong, while continuing to operate fine chemicals plants in Kingsport and in Batesville, Ark. (C&EN, April 23, page 12). However, Eastman will no longer produce to special order for the drug industry.

At Bayer AG of Leverkusen, Germany, and DSM Fine Chemicals in Sittard, the Netherlands, however, enthusiasm for fine chemicals continues unabated. Both companies are pushing expansions and acquisitions. Rudolf Hanko, who is head of fine chemicals at Bayer, gave his views on the current business situation at ChemSpec Europe 2001 in Amsterdam.

Of cGMP capacity worldwide, he said: "There is a tremendous market out there, but it's fragmented. Some companies underestimated the cost of entry. No one in custom manufacturing has more than 1% of the market, but there are a lot of firms involved."

And he said of future prospects: "I think there will be growth of 5% per year. For pharmaceutical fine chemicals, growth rates of 10% per year over the next five or six years are not unreasonable." Hanko ascribed such strong growth to the fact that start-ups of virtual companies, which are discovery companies with no production capacity, continue increasing.

But in Amsterdam he did not minimize present hardships: "Last year was a disaster, to put it mildly," he said. "We survived because we were spread out. We weren't reliant on the pharmaceutical industry. Other firms are closing because they priced their products irresponsibly to gain market share. They paid the price. You can't build a business that way."

More additions to Bayer's ZeTO--Zentral Technikum Organikum, the firm's central pilot plant--are in the offing. Hanko said the company will make a decision in the third quarter of 2001 whether to build a small, general-purpose plant geared to make the 30 to 50 kg per year of drug substances needed for the first phase of clinical studies.

If Bayer's Hanko seems upbeat, Henk Numan, head of DSM Fine Chemicals positively warms to the subject. Speaking to C&EN in Sittard, Numan says that DSM is restructuring, selling off petrochemicals and plastic resins to become a wholly fine and specialty chemicals company with sales of 10 billion euro (currently worth about $8.6 billion) by 2005.

"We're now 5 billion or 6 billion euro," Numan says of the fine chemicals business, "so we must sell petrochemicals and acquire specialty chemicals." Since 1987, DSM has been on the acquisition trail, buying Andeno (the Netherlands), Chemie Linz (Austria), Deretil (Spain), Gist-Brocades (the Netherlands), and Catalytica (U.S.).

Expectations by industry observers and recommendations by consultants have been to sell or close several plants and research centers. But Numan is determined to keep them all. He says Catalytica's "lyophilization and sterile-fill capacity is interesting, because it fits in with our prior biotechnology. Catalytica means that we get into bulk active drugs. For example, we will manufacture the dosage form of a new Eli Lilly product."

An important use of DSM's facilities is to make products for client companies, Numan points out. "We have 66 new products in our company," he explains. "That means that we have the number to give us stability. Clients' compounds help to load our plants." Numan is also enthusiastic about the future, despite recent problems. "A lot of launches were delayed," he tells C&EN, "but we shall see results from drug companies' big pipelines." He also sees promise in virtual companies: "We must look at these firms, because many of them have good compounds. With such small firms, it means that we must really do our homework."

And DSM continues to pursue innovation: "Before, we were doing chemistry invented 25 years ago. Now we are doing reactions in our plants that were only published in the past year." Also on the subject of innovation, Ellen de Brabender, who is head of research at DSM Fine Chemicals, explains the rationale for maintaining all of the research sites where they are.

"From the beginning of 2001," she says, "we have four research groups spread out over nine sites." By research she means process chemistry, mostly directed at new business development. At four of the sites, the company has what it calls a triangle: process development, piloting, and commercial-scale production.

In order to coordinate the expertise of the company among so many different sites, DSM has global competence managers. These managers are in charge of knowing what the company has in certain technology areas. For example, Q. B. (Rinus) Broxterman is a global competence manager for amino acids and chiral technology. Those managers also decide where to continue to develop technology areas and not leave it to local people.

One objective of this management organization is speed, de Brabender says. "We do parallel projects for speed," she explains. "We develop an enzyme and a process. Customers want eight days from an inquiry to a proposal, not two weeks. So we need very good information technology systems."

Though the fine chemicals industry is going through a trough of activity at present, fine chemicals producers continue to develop their abilities to produce to special order for customers. Firms are still introducing new intermediates and reagents, hoping to induce customers to adopt them. And academic chemists continually invent new chemistries that fine chemicals firms license and put into commission.

Among custom producers, the Dow Custom & Fine Chemicals business unit in Midland, Mich., has shortened--to three steps from nine--a process for making the cough suppressant glaucine from the commercially available alkaloid papaverine. In addition, the AMCIS subsidiary of Solutia Pharmaceutical Services in Bubendorf, Switzerland, has converted from stoichiometric to catalytic a reduction for making an intermediate for antiglaucoma drugs. Avecia, Billingham, England, has developed a biocatalytic resolution of sulfoxides that are chiral at sulfur. Mercian Corp. of Tokyo uses microorganisms in a new route to (S)-pipecolic acid. And Lonza has found a way to carbonylate chloro pyridines to carboxylic esters.

The Dow Custom & Fine Chemicals business is a month-old combination of Dow's former Contract Manufacturing Services with Dow's other subsidiaries, Angus Chemical and Ascot. The company has named George Biltz as vice president in charge of the new business unit. Biltz remains president of Angus as well.

The task at Dow was to start with the 1-benzylisoquinoline ring system of papaverine and saturate the heterocyclic ring. Next, an oxidation closed the additional fused ring of intermediate laudanosoline. Finally, a methylation and salt adjustments yielded glaucine as the sesquiphosphate salt.

Dow process chemists telescoped the four-step conversion of papaverine hydrochloride to laudanosoline hydrobromide to one step. The previous process had involved separate steps, each with losses resulting from isolations of solids. They next doubled the yield of the oxidation step. The result of these efforts was a tripling--to 35%--of the overall yield of glaucine from papaverine.

At Solutia AMCIS, Research & Development Director Thomas E. Waldman tells C&EN that a pivotal step in making an antiglaucoma drug intermediate is the reduction of a thieno sultam ketone to an (S)-alcohol. As Waldman explains, "Solutia Pharmaceutical Services was created in early 2000 with the acquisitions of CarboGen Labs and AMCIS with the goal of providing faster drug development services in support of clinical trials and niche manufacturing."

Comparing the two operations, Waldman says, "AMCIS is a service-focused, FDA-inspected operation with highly flexible production equipment ranging from 50 L up to 1,600 L, forming an ideal complement to the kilo-lab activities of CarboGen. While the chemists at CarboGen are focused on delivering the first kilogram of active pharmaceutical ingredient (API) as fast as possible, AMCIS has a longer term view to production and robust manufacturing routes. With over 20 years of experience providing development and API production services, AMCIS has developed considerable expertise, especially in the area of chiral reductions."

In particular, the ketone reduction was previously done with stoichiometric amounts of (+)-diisopinocampheylboron chloride, which was costly. Process chemists in Bubendorf substituted far less expensive borane-tetrahydrofuran complex as the reducing agent and induced asymmetry in the reduction by using a boroxazolidine catalyst derived from (S)-proline.

ASYMMETRIC CHEMICAL reductions are one way to get to optically active products. In another, Avecia of Billingham has had great success in whole-organism fermentative asymmetric reductions. Robert A. Holt, who is research manager of Avecia's biocatalysis group, described some of the company's projects at the Chiral USA 2001 conference in Boston in May.

One subject that Holt focused on was chiral sulfoxides, which are of increasing importance in such drugs as AstraZeneca's Nexium brand of esomeprazole, an oral proton pump inhibitor to treat gastrointestinal irritation. The biocatalysis group settled on kinetic resolution of racemic sulfoxides as the best approach.

"Although resolution is in principle a less attractive option than asymmetric synthesis," Holt said, "there are instances where the resolution approach has advantages. For example, an asymmetric reaction may fail to yield the desired enantiomeric purity, whereas with a resolution, there is the option to trade decreased yield for increased enantiomeric purity."

As for the issue of throwing away half of a resolved racemate, Holt pointed out, "the by-product of reductive resolution of sulfoxides is a nonchiral sulfide, the chemical reoxidation of which is generally a trivial exercise, allowing effective recycle of the reaction product to racemic sulfoxide."

Because sulfoxides are atypical substrates in nature, Avecia researchers screen soil samples randomly to find activity rather than try to target the activity by genetic engineering. To screen for sulfoxide-reducing bacteria, they incubate soil samples with the exclusion of air. Thus, rather than oxygen, bacteria have to use the dimethyl sulfoxide added to the medium as the terminal electron acceptor during metabolism of glucose.

Following growth in liquid culture, they subculture bacteria on agar plates, testing for dimethyl sulfide formation. "It's pretty easy to tell," Holt said with a smile, referring to the stench of dimethyl sulfide.

The Avecia workers find that there are bacteria that will give either the (R)- or (S)-sulfoxide on further testing with racemic methyl p-tolyl sulfoxide. Thus Escherichia coli gives greater than 98% enantiomeric excess (ee) of (S)-methyl p-tolyl sulfoxide when the reduction is run to 70% completion, whereas Rhodobacter capsulatus gives greater than 98% ee of the (R)-sulfoxide at 56% completion.

Also new in the resolution of chiral sulfoxides is a liquid chromatographic column packing from Regis Technologies, Morton Grove, Ill. Developed by organic chemistry professor Francesco Gasparrini at the University of Rome, the material is a diamide of 3,5-dinitrobenzoic acid with either isomer of trans-1,2-diaminocyclohexane. In addition to sulfoxides, the material also separates chiral selenoxides, phosphine oxides, and phosphonates.

Mercian's (S)-pipecolic acid process is another use of the enantioselective power of bacteria. Riichi Kanemaru, manager of the company's pharmaceutical and chemical division, described the process to Outsource 2001. It uses cultures of E. coli with L-lysine as starting material. The company has spliced the gene for lysine 6-aminotransferase from Flavobacterium lutescens into E. coli.

This enzyme is part of a metabolic pathway in F. lutescens that oxidizes the -amino group of lysine to L-homoglutamic acid [(S)-2-aminohexanedioic acid]. The intermediate in this oxidation is an amino acid aldehyde, which is in equilibrium with the ring-closed Schiff base, tetrahydropicolinic acid. But in E. coli, this intermediate is intercepted by that organism's own piperazine-6-carboxylate reductase and reduced to (S)-pipecolic acid.

The competing process for (S)-pipecolic acid belongs to Lonza. That firm starts with picolinonitrile, which it converts by turns into picolinamide, racemic pipecolamide, and (S)-pipecolic acid. The method of that last conversion uses fermentation with Pseudomonas species.

Elsewhere in biocatalysis, BioCatalytics, Pasadena, Calif., has added three nitrilases to its catalog of enzymes for industry. The three are available in a kit of 50 mg each for customers to screen their substrates. Among structural types of nitriles hydrolyzed to carboxylic acids by the enzymes are acrylonitrile, (R)--chloro--hydroxybutyronitrile, ethyl cyanoacetate, -naphthylacetonitrile, pelargononitrile, -phenyl-butyronitrile, m-phenylenediacetonitrile, succinonitrile, and p-tolylacetonitrile.

Lonza itself has developed new chemistry to carbonylate chloro pyridines to carboxylic esters. Such carbonylation has succeeded in the past only with more costly bromide and iodide starting materials. For example, starting with 2,3-dichloropyridine, 2,3-dichloro-5-trifluoromethylpyridine, or 2,3-dichloro-5-methoxymethylpyridine, Lonza chemists use palladium catalysts, carbon monoxide, and ethanol to make either the ethyl pyridine-2-carboxylates or the diethyl pyridine-2,3-dicarboxylates. The product selectivity for carboxylate or dicarboxylate esters is determined by different phosphine ligands in the catalyst.

CATALYSIS Solvias develops asymmetric catalysis ligands in its Basel plant.
IN DEVELOPMENT DSM Fine Chemicals' new pilot plant completes the triangle of process development, piloting, and commercial-scale production in Venlo, the Netherlands.
ONE SOURCE of catalysts for Lonza's processes is Solvias, which is also based in Basel. Solvias is the spun-off catalyst research department of the former Ciba-Geigy. The company now performs the dual role of custom chemicals production and development for sale of asymmetric catalyst ligands.

Hans-Ulrich Blaser, research director and chief technical officer at Solvias, demonstrates the company's abilities by describing a simplified asymmetric synthesis of ethyl (R)--hydroxy--phenylbutyrate. That compound is an intermediate in making angiotensin-converting enzyme inhibitors to treat high blood pressure.

The Solvias researchers begin with the inexpensive starting materials acetophenone and diethyl oxalate, which undergo base-catalyzed reaction to give ,-diketo- -phenylbutyrate. That ester undergoes asymmetric hydrogenation catalyzed by alumina that has been impregnated with both platinum and the quinine alkaloid hydrocinchonidine. The product (R)--hydroxy ester next undergoes palladium-catalyzed hydrogenation to reduce the benzylic keto group to methylene.

Noteworthy is that the asymmetric hydrogenation goes in only 88% ee. The phase diagram of the enantiomers, however, is such that a mere recrystallization from diisopropyl ether raises the ee to greater than 99%.

International Specialty Products of Wayne, N.J., is a company that has moved to acquire new chemistry. The acquisition was of FineTech in Haifa, Israel (C&EN, June 18, page 13). FineTech specializes in chiral chemistry and derivatives of adamantane and of polynuclear aromatic hydrocarbons. Because asymmetric syntheses frequently need low temperatures to ensure ee, the acquisition should fit in well with ISP's low-temperature reactors in Columbus, Ohio.

Following the acquisition, Arie L. Gutman remains both president and scientific director at FineTech and professor of organic chemistry at Technion-Israel Institute of Technology, Haifa. Among Gutman's recent technological achievements are processes for (R)-1-aminoindan, an intermediate for such drugs as rasagiline for Parkinson's disease; for (S)-7-methoxy-2-aminotetralin, an intermediate for drugs to treat obesity and depression; and for (S)-5-methoxy-3-aminochroman, an intermediate for drugs like alnespirone to treat anxiety and depression.

To make the aminoindan, Gutman tried enzyme-catalyzed acylation of racemic amine with an activated propionate ester. But background nonenzymatic acylation degraded the ee. He also tried asymmetrically induced reductive alkylation of (R)--phenethylamine with indanone, followed by hydrogenation to cleave the phenethyl group. But the product amino indan is itself a benzylic amine, and so there is significant destruction of product by cleavage of the indan group.

Gutman's solution is reductive alkylation of indanone with benzylamine and sodium borohydride. He resolves the racemic benzylaminoindan with l-tartaric acid and hydrogenates the (R)-isomer to the desired (R)-1-aminoindan. He racemizes the unwanted (S)-benzylamino isomer with potassium tert-butoxide.

Gutman makes the aminotetralin and aminochroman by similar methods. For example, he alkylates 7-methoxy-2-tetralone with (R)--phenethylamine. The intermediate is an enamine, which he reduces to a single enantiomer amine with catecholborane (1,3,2-benzodioxaborole) over 10 hours at –70 °C. Hydrogenation cleaves the phenethyl group and frees the (S)-aminotetralin.

IN ADDITION to new chemistries, fine chemicals producers are introducing new intermediates and reagents to attract customers. For example, Eastman Chemical is making cyclopropyl-substituted amino acids. Sigma-Aldrich Fine Chemicals, St. Louis, is offering a new line of 35 isocyanates, 21 isothiocyanates, and 10 chloroformates in 100-kg amounts or greater. Also, the company Dr. Eckert of Hallbergmoos, near Munich, is offering 16 isocyanates and 11 isocyanides (R--NC) in up to 500-g amounts off the shelf, or in tons to special order. In addtion, Wacker-Chemie, Munich, is offering new silylating agents for protection of functional groups.

Eastman's entry to cyclopropane derivatives is via cyclopropanecarboxaldehyde, which the company makes from 3,4-epoxybutene obtained from epoxidation of butadiene. Senior research associate Neil W. Boaz described production processes for single-enantiomer cyclopropylglycine and cyclopropyl-- and --alanines at Chiral USA 2001. These processes were developed in cooperative research with Oxford Asymmetry International, Abingdon, England, which has since been acquired by drug firm Evotec Biosystems of Hamburg, Germany, and is now known as Evotec OAI.

The Eastman/OAI experience with the three compounds is a reminder that in making single enantiomers, there is no one best method. The best route to cyclopropylglycines turns out to be an asymmetric Strecker synthesis; the best route to cyclopropyl-a-alanines is an asymmetric hydrogenation; and the best way to cyclopropyl-b-alanines is classical resolution of the racemate by diastereomeric crystallization.

Thus, reaction of the aldehyde with (S)--phenethylamine gives a Schiff base, which reacts with potassium cyanide to yield an amino nitrile. This product is a 3:1 mixture of the (S,S)-diastereomer with the unwanted (R,S)-diastereomer, which Boaz says cannot be improved. But hydrolysis to the amino acid yields a solid amino acid that can be upgraded to more than 98% (S,S)-diastereomeric excess by simply stirring with methanol. Hydrogenation cleaves the phenethyl group, producing 35% overall yield of (S)-cyclopropylglycine. The process is economical because the aldehyde is so inexpensive.

Condensation of the aldehyde with hippuric acid gives an azalactone, which is opened by sequential treatment with benzyl alcohol, tert-butoxycarbonic anhydride, and hydrazine to the Boc-protected benzyl ester of cyclopropylacrylic acid. Hydrogenation of that unsaturated ester with a rhodium chelate of a proprietary asymmetric ligand yields the corresponding derivative of (S)-cyclopropyl-a-alanine. The formation of the azalactone goes in only 30% yield, but the low cost of the raw materials vindicates this process also.

Finally, reaction of the aldehyde with ammonium acetate and malonic acid gives an amino diacid, which can be decarboxylated to racemic cyclopropyl--alanine. Classical resolution failed with the amino acid and ethyl ester, but succeeded with isopropyl ester. Hydrolysis of the resolved esters resulted in overall yields of 15 to 18% of each enantiomeric amino acid.

The isocyanates and chloroformates newly available in amounts of hundreds of kilos from Sigma-Aldrich come from the company's Bethany, Conn., plant. The company got the plant on acquisition of Carbolabs, a custom chemicals producer with expertise in phosgene chemistry. Isocyanates result from reaction of amines with phosgene, chloroformates from reaction of alcohols, and isothiocyanates from reaction of primary aromatic amines with thiophosgene.

Aliphatic isothiocyanates arise from reaction of primary aliphatic amines with carbon disulfide and a base. Sigma-Aldrich plans to develop the ability to make aliphatic isothiocyanates later this year and will concentrate on "high-end" compounds, meaning that the company will not make workhorses such as methyl isothiocyanate.

The isocyanates and isocyanides newly available from Dr. Eckert likewise derive from phosgene. The company's isocyanides come from reaction of amino acid esters with formic acid to give formamides, which are then dehydrated to isocyanides with phosgene.

Whereas the usual phosgene production process is reaction of carbon monoxide and chlorine, Dr. Eckert makes it as needed by thermal decomposition of triphosgene--bis(trichloromethyl) carbonate--which it makes in turn by photochemical chlorination of dimethyl carbonate. Andreas Anthony, who is director of marketing and sales, tells C&EN that the company has a proprietary initiator for triphosgene decomposition that yields 3 moles of phosgene rather than 1 mole of phosgene plus carbon tetrachloride and carbon dioxide.

AMONG NEW silylating agents offered by Wacker-Chemie is triethylsilyl chloride. Jörn Winterfeld, who is development and technical service manager for silanes, tells C&EN that the triethylsilyl group is more stable to reaction conditions than the trimethylsilyl group, but less stable than the tert-butyldimethylsilyl group.

He cites the advantages of this property in an intermediate--encountered at the end of a synthesis of paclitaxel--that contains all three groups. Treatment with acid removes the trimethylsilyl group. Hydrogen fluoride/pyridine selectively cleaves the triethylsilyl group. And tetrabutylammonium fluoride removes the last group.

Also new from Wacker is 1,1,3,3-tetraisopropyl-1,3-dichlorosiloxane. This bidentate silylating group is useful to protect the C-2 and C-3 hydroxyl groups of ribosides simultaneously. Finally, for less reactive hindered secondary and tertiary alcohol substrates, Wacker has trimethylsilyl and tert-butyldimethylsilyl trifluoromethanesulfonates. Availability of these reagents lets chemists order the protection of hydroxyl groups by strategic use of chlorides and trifluoromethanesulfonates. A chemist can use a silyl chloride of one type to protect a primary alcohol, followed by a different trifluoromethanesulfonate for a secondary or tertiary alcohol.

In addition to the new chemistries and intermediates coming out of industrial laboratories, there is new technology arising in academic centers as well. For example, organic chemistry professor Eric N. Jacobsen of Harvard University is applying principles of bimetallic catalysis to, for example, kinetic resolution of epoxides.

In this reaction, cobalt(III) chelated by an enantiomeric ligand catalyzes the addition of water to one enantiomer of a racemic epoxide preferentially. The products are the other enantiomer of the epoxide plus the glycol corresponding to the epoxide enantiomer that is attacked. The reaction can be run in such a way as to maximize the ee of the epoxide or glycol product.

But in such reactions, as Jacobsen told the Chiral USA 2001 conference in Boston in May, one transition-metal ion may complex the attacking nucleophile such as water, while another ion may hold the epoxide oxygen. If the two metal ions were in the same catalyst molecule, their cooperation might enhance the catalytic efficiency and enantioselectivity of the reaction.

Jacobsen has now made versions of his epoxide resolution catalyst that incorporate two or more cobalt ions [J. Am. Chem. Soc., 123, 2687 (2001)]. His original catalyst ligand is a double Schiff base of either enantiomer of 1,2-diaminocyclohexane with 3,5-di-tert-butylsalicylaldehyde. In the polymetallic version, the salicylaldehyde has a hydroxyl group at position 5 in place of one tert-butyl group. He uses these hydroxyl groups to link two or more ligand molecules together in macrocycles with heptanedioic acid units. He demonstrates the efficacy of the polymetallic version by converting the usually intractable racemic cyclohexene oxide to a trans-1,2-cyclohexanediol in 98% yield and 94% ee.

Harvard's patents on Jacobsen's enantioselective chemistries are licensed to Rhodia ChiRex, Boston. At ChemSpec Europe 2001 in Amsterdam last month, representatives of Rhodia ChiRex and Synetix announced that they had agreed for Synetix to develop a version of the Jacobsen epoxide resolution catalyst that is immobilized on a zeolite support. Synetix is the catalyst development subsidiary of ICI.

Such immobilization of the homogeneous catalyst would ease separation of catalyst from reaction mixtures by filtration. Such separability would minimize contamination of organic products by metals. Immobilization would also minimize losses of precious metals chelated by catalyst ligands.

In the Synetix immobilization technology, the company's chemists replace a cationic site in the pore of a zeolite aluminosilicate cage by a metal such as cobalt. Then they chelate the bound metal with an organic ligand. As Ian Shott, president of the ChiRex manufacturing division, puts it: "Rhodia ChiRex will now be able to cost-effectively manufacture a wider variety of chiral chemicals and expand our outreach to customers in more market sectors." The new immobilized catalyst will be made for Rhodia ChiRex by Synetix in Billingham, and used by Rhodia ChiRex at its plant in Dudley, England.

Though such catalysts as Jacobsen's are proprietary for commercial use, patent holders often license Strem Chemicals of Newburyport, Mass., to make and sell them for research use. For example, two new products from Strem are the chromium(III) chelates of the Jacobsen ligand based on each enantiomer of trans-1,2-diaminocyclohexane. These catalysts are useful for such reactions as asymmetric addition of trimethylsilyl azide to epoxides.

Also new to the Strem catalog are second-generation ruthenium carbene catalysts for olefin metathesis developed by organic chemistry professor Robert H. Grubbs of California Institute of Technology. In addition to selling out of a catalog, Strem does process development and custom synthesis under cGMP.

Strem recently tripled its cGMP capacity. "We've been manufacturing under cGMP for more than 10 years," Vice President Ephraim S. Honig says, "but over the past few years, we've seen increased interest for these services. We've had to be selective in the projects we could undertake, and we saw an opportunity to grow the business and provide faster service to our pharmaceutical customers. The addition of our new cGMP suites now provides more flexibility for managing multiple projects of varying complexity."

BESIDES THE NEWEST technology from Jacobsen's laboratory, other academic researchers have weighed in with new chemistry that may become commercial in a short time. In one case, a chemist at the Max Planck Institute for Coal Research in Mühlheim-an-der-Ruhr, Germany, has developed a new cross-coupling reaction that yields substituted arylacetic acids. Such acetic acids are components of the "profen" class of antiinflammatory drugs.

In another instance, a team at Kansai University, Osaka, Japan, has devised a three-component reaction that combines three reaction steps into one by activating C-H bonds adjacent to imine groups. Such multicomponent reactions are useful for fast syntheses of combinatorial libraries of compounds.

In a third instance, a group at the University of British Columbia in Vancouver reports mutant enzymes that catalyze fluorination of organic substrates. The finding suggests that biologically active fluorine compounds may be made this way.

And finally, workers at the University of Kansas, Lawrence, have devised new means to remove ruthenium from reaction mixtures. Such a method is useful to remove highly colored catalyst residues from drug intermediates following such reactions as olefin metathesis.

Assistant chemistry professor Lukas J. Goossen in Mühlheim described his cross-coupling reaction to the American Chemical Society in San Diego last April. In preparation of ethyl phenylacetate itself, benzeneboronic acid reacts with ethyl bromoacetate to give a 67% yield. The most successful catalyst is a palladium(II) salt and tri-1-naphthylphosphine. There is also a 31% yield of biphenyl, however, and a small amount of benzene.

Demonstrating the selectivity of the reaction, Goossen gets an 89% yield of 4-bromobutyl phenylacetate on coupling of benzeneboronic acid with 4-bromobutyl bromoacetate. Thus the bromine atom on the acyl group reacts, but that on the alkyl group does not.

In a three-component reaction invented at Kansai University, organic chemistry professor Yasutaka Ishii and coworkers combine an aldehyde, a primary amine, and an acetylene, plus an iridium(II) catalyst [Angew. Chem. Int. Ed., 40, 2534 (2001)]. The aldehyde and amine react to form a Schiff base. The iridium catalyst activates a C–H bond adjacent to the imino group. That C–H combination adds across the acetylenic triple bond to form an olefin. For example, butyraldehyde, n-butylamine, and 1-octyne yield 72% of the Schiff base of butyraldehyde and 4-amino-5-methyleneundecane.

Chemistry-biochemistry professor Stephen G. Withers and coworkers in Vancouver find that modifying amino acid sequences of a bacterial glucosidase and mannosidase produces enzymes that mediate conversion of 2,4-dinitrophenyl-b-d-glucoside or -mannoside to a-d-fluoroglucose and -mannose respectively [J. Am. Chem. Soc., 123, 4350 (2001)].

The ruthenium-removal technology is the achievement of medicinal chemistry professor Gunda I. Georg, postdoctoral fellow Yu Mi Ahn, and graduate student KyoungLang Yang [Org. Lett., 3, 1411 (2001)]. Following an olefin metathesis reaction, they add 50 equivalents each of triphenylphosphine oxide and DMSO to the reaction mixture, based on the millimoles of ruthenium used. This procedure results in complexation of colored catalyst residue, which is left behind on filtration through silica gel as a hexane-ethyl acetate solution.

Thus, although the market growth in fine chemicals has flattened, there is no letup in introduction of new building blocks and reagents to product lines and no slacking off in inventing whole new chemistries to make fine chemicals to special order. This continued vigorous innovation goes on not only in the laboratories of fine chemical producers, but also at universities worldwide.

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Drug development
Pharmaceutical firms juggle large steady-state product loads
NO. OF COMPOUNDS UNDER DEVELOPMENT YEAR 1 YEAR 2 YEAR 3 YEAR 4 YEAR 5 YEAR 6 YEAR 7 YEAR 8
Preclinical 30 30 30 30 30 30 30 30
Phase I 18 18 18 18 18 18 18
Phase I–II 12 12 12 12 12 12
Phase II 10 10 10 10 10
Phase II–III 8 8 8 8
Phase III (1) 6 6 6
Phase III (2) 4 4
Launch 3
Steady-state product load 91
SOURCE: Bristol-Myers Squibb

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MEETINGS
Expositions And Symposia Highlight Fine Chemicals

July 15–8. International Symposium on Chirality. Orlando, Fla. Contact Barr Enterprises, P.O. Box 279, Walkersville, MD 21793; (301) 898-3772, fax (301) 898-5596, e- mail: janetbarr@aol.com, website: http://www.chiral.com.

Sept. 25–26. ChemSource. Manchester, England. For the exposition, contact DMG World Media, 2 Queensway, Redhill, Surrey RH1 1QS, U.K.; phone 44 1737 855523, fax 44 1737 855474, e-mail: sallyembling@uk.dmgworldmedia.com. For the symposium, contact the Royal Society of Chemistry, Howell Croft, Cow La., Norley, Frodsham, Cheshire WA6 8PW, U.K.; fax 44 1928 788071, e-mail: ruth@lane2.freeserve.co.uk.

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

Oct. 11–12. Chiral Europe 2001. Contact Scientific Up-date, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, U.K.; 44 1435 873062, fax 44 1435 872734, e-mail: sciup@scientificupdate.co.uk.

Nov. 12–14. ChiraSource. Philadelphia. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; (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.; 44 1372 841010, fax 44 1372 841012, e-mail: Paulfolio@aol.com.

Feb. 26–March 1, 2002. Informex. New Orleans. Contact Synthetic Organic Chemical Manufacturers Association, 1850 M St., N.W., Washington, DC 20036; (202) 721-4100 fax (202) 296-8120, e-mail: diane.mcmahon@socma.com.

April 28–30, 2002. Chiral Asia 2001. Hong Kong. Contact Scientific Update.

June 26–27. 2002, ChemSpec Europe. Basel, Switzerland. For the symposium, contact DMG World Media. For the exposition, contact British Association for Chemical Specialities, Gate House, White Cross, Lancaster LA1 4XQ, U.K.; 44 1524 849606, fax 44 1524 849194, e-mail: enquiries@bacsnet.org.

Oct. 14–15, 2002. Chiral USA 2002. Boston. Contact Scientific Update.

Oct. 16–17, 2002. Outsource 2002. Boston. Contact Scientific Update.

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