COVER STORY
SPOTLESS This filter-drier in a clean room at Lonza's plant in Visp, Switzerland, complies with current Good Manufacturing Practice and is used in custom manufacture of pharmaceutical intermediates and active ingredients.
FINE CHEMICALS Midway through 2002, producers are cautiously optimistic about business, adopting different strategies to achieve growth A. MAUREEN ROUHI, C&EN WASHINGTON
O
BSERVERS STILL PREDICT A LACKLUSTER YEAR FOR
the fine chemicals industry, although perhaps a little better than 2001. The basic drivers of the industry have not changed since the beginning of the year. The industry still suffers from overcapacity and low demand. And increasingly, U.S. and European producers face aggressive competition from Asia. "There's still no light at the end of the tunnel," says Peter Pollak, a fine chemicals business consultant based in Reinach, HTTP://PUBS.ACS.ORG/CEN
Switzerland, about the prospects for the industry And Enrico T. Polastro, vice president and senior industry specialist at Arthur D. Little Benelux, expects the worsening of results that began in 2000 to continue through 2002 across all industry segments, from intermediates to active ingredients and from multiclient products to custom synthesis. Industry insiders give mixed reviews. Depending on who's talking, the outlook for the rest of2002 ranges from lousy to great. Companies that supply upstream materials or nonpharmaceutical intermediates or products have felt the onslaught of Asian competition the most. They are desperate to figure out what more they can C & E N / JULY 2 2 , 2002
45
COVER STORY offer when buyers are routinely getting Many companies have been similarly hit few new compounds from drug compa half-price bids from Asian companies. by product withdrawals. For example, at nies, the situation has led to low capacity about this time last year, two drugs for Away out is to reduce dependence on utilization in the industry" which FMC Lithium had been sup that market. That's what Regis plying synthetic reagents failed after Technologies did when it decided IMAGE MAKER launch. "It was painful. We had noth in 1993 to refocus its business from FMC Lithium aims to make a name in directed ing tofillthe gap," Gregory R. Harm, chromatography and nonpharmaortho-metallations... marketing and sales director for ceutical chemical products to phar organometallics, tells C&EN. "But maceutical custom synthesis. DMG DMG this time, we're coming back a bit "Being a small chemical manu RLi Electrophile (E) because of new projects involving facturer and competing on price is statin drugs." not a fun place to be," says Regis' president, LouisJ. Glunz IV ' W h e n 'We're not out of the woods yet" we became a small pharmaceutical is the view from the small company ... which have been used by companies such manufacturer competing more on Organic Technologies. Jack Ethas Merck to make drug intermediates value added, we became a winnable eridge, vice president for sales and proposition. We're not experienc marketing, says sales are down 25% ing any pains." from last year. Adding to the prob lems ofproduct failures, delays, and The shift has produced dramat λ—MM / withdrawals are U.S. tax and regula ic results, Glunz says. In 1993, sales tory policies, which have created an were $2.6 million, with 58% from uneven playing field for U.S. com chromatographic products. This panies. Disputes between customer year, Glunz projects that sales will companies also have roiled some reach $ 14 million, up 30% from last markets as people joust for positions year. And 86% of that will come based on legal issues, he adds. "The from custom synthesis. The com litigious climate adversely affects pany is running out of capacity and small businesses like us." will be building a pharmaceutical production plant that will be oper ational in 2004. RECOVERY WILL vary from com Asian competition for pharma pany to company, Polastro says. In ceutical intermediates and active pharmaceutical custom manufac ingredients is still manageable. Nev turing, for example, companies that ertheless, customers are more ag are doing well are those that chose gressive than ever in demanding low winning products and customers. nBu prices. This trend—along with the But that does not guarantee repeat overcapacity and low demand success year after year. brought about by consolidation in Without a crystal ball to pick win the pharmaceutical industry and ners, makers of fine chemicals in DMG = directing metallation group the slow rate at which new chemi crease their chances ofsuccess in dif FG = functional group cal entities are being developed and ferent ways. For some, success lies in Losartan potassium iPr = isopropyl approved by the Food & Drug Ad serving a diverse range of customers. nBu = n-butyl ministration (FDA)—creates a chal 'Albemarle's stock price has dou lenging business climate. bled since mid-2001 because we've HIGHLY PURE "So far, this year has been better performed well in this tough envi Products of SNPE route have negligible chlorine than last year," says Peter Nagler, ronment," says Scott Martin, vice president of Degussa Fine Chemi president and general manager for cals. "But I do not see that the econ fine chemistry services. He says the OH omy will all of a sudden boom for a success is due to Albemarle's diverse CI cr 100% turnaround. We are cau portfolio, from polymer additives to NHo tiously optimistic." active ingredients. Two major prod Η χ0 ucts, ibuprofen and naproxen, are "Folks are having a tough time," L-Leucine Chlorine, < 0.05% recession-proof, he says. Production Simon Edwards, vice president of of both is "running very hard," he sales and marketing for Lonza's ex HCl adds. He estimates that current ca clusive synthesis business, tells a pacity utilization is about 80%, al C&EN. "We've had our share of though custom manufacturing products that have been pulled or Bornyl chloride a-Pinene plants are only about 60% occupied. put on hold by the FDA. Along with
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C & E N / JULY 2 2 , 2002
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Jai P. Nagarkatti, president of SigmaAldrich Fine Chemicals (SAFC), says sales through the first quarter of 2002 are on track at 12% growth per year. That has been achieved by not depending on one indus try sector for growth, he adds.
According to Nagarkatti, 6 0 % of SAFC's revenues come from chemically synthesized compounds and 40%frombiochemicals—proteins, cell culture media, and biological buffers. Most products are multiclient, but custom synthesis is grow
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ing. Also key are chemicals for electronics and other nonpharmaceutical applications, where the company's strengths—handling of air-sensitive reagents, custom formula tion of cell culture media, and protein ex traction from biomass and purification— can be applied in large scales. Diversification works with small com panies, too. An example is the German company Organica, with annual sales in 2001 ofabout $8 million. Despite increased competition in the past three years, sales have grown at an average of 15-20% per year until last year, says its managing director, Bodo Schulze. 'The main reason is that we have diverse customers," he says. Although Organica mainly supplies the imaging industry, it occupies a niche of high-value dyes used for information stor age in compact discs and digital video discs. It also sells azide-chemistry-based intermediates off the shelf or as custom products. And it produces a diagnostic dye—indocyanine green—as an active pharmaceutical ingredient (API). Compared with mid-2001, Organica's sales so far are flat. But with the German economy poised for growth in the second half of the year, Schulze says, "we are still hopeful for positive growth by year's end." OTHER COMPANIES find strength in spe cial niches, usually based on core tech nologies. And more and more, these com panies are cultivating the natural extensions of those core expertises. For example, FMC Lithium is known as a supplier of organolithiums. Now, Hahn says, the company is extending that knowl edge to other organometallics or other reagents made from organolithiums. And it is pursuing opportunities to prepare in termediates through syntheses involving organometallics as reagents. Hahn says: "We have been trying to set a new image by calling ourselves 'more than lithium.'We want to emphasize that we're staying with our lithium roots but stepping beyond to manufacture other reagents and to do organic synthesis." Along the same vein but in a different area, Organic Technologies is capitalizing on its expertise in custom distillation, ex traction, and purification. The company has applied for process patents for pure nutraceutical products, high-performance fuel or propellant components, and phar maceutical intermediates. Interest in this capability has increased, Etheridge says. "Petrochemical companies that have scaled back their pilot plants come to us for custom distillation of new products." Intense interest is coming from HTTP://PUBS.ACS.ORG/CEN
degussa Fine Chemicals How to stay in stride with your guanylations If you do guanylations, then you want a reliable cyanamide supplier. But perhaps you want a manufacturer that can do more. One that can deliver the product in the quantity, purity, and form you need. One with know-how that can tailor products for you. One that can solve problems quickly. It's a fine art, and we at Degussa Fine Chemicals strive to excel at it - we don't want you to lose a step. For more information please contact Degussa Fine Chemicals, the world's leading manufacturer of cyanamide. e Fine Art of Fine Chemicals.®
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(3/?)-(+)- 96+% (GC) [E0433] (3S)-(-)- 96+% (GC) [E0434]
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3-(Dimethylamino)pyrrolidine (3/?)-(+)-95+% (GC) [D2149] (3S)-(-)-96+% (GC) [D2193]
Ri=H,R2=Me 1-Benzyl-3-(melhylamino)pyrrofidine
3-(Trifluoroacetamido) pyrrolidine Hydrochloride
(3R)-(-)- 98+% (GC) [B1582] (3S)-(+)- 98+% (GC) [B1583]
(3K)-(+)- 98+% (Τ) [Τ1369] (3S)-(-)-98+% (Τ) [Τ1366]
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1-Benzyl-3-aminopvrrolidine (3R)-(-)- 98+% (T) [ A U 7 3 f ' (3S)-(+)-98+%(T) [ A l l M k ,
(3R)-(+)- 98+% (Τ) [Α1169] (3S)-(-)-98+% (Τ) [Α1170]
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Ri =H,R2=Et 1 -Benzyl-3-(ethylamino)pyrrolidine (3R)-(-)- 95+% (GC) [B1580] (3S)-(+)-95+% (GC) [B1581]
Tokyo Kasei Kogyo Co., Lid., Jpn. Kokoi Tokkyo Koho JP 90-218664 (1990) ; Tokyo Kasei Kogyo Co., Lid., Jpn. Kokai Tokkyo Koho JP 88-41453 (1988) ; Tokyo Kasei Kogyo Co., Lid., Jpn. Kokai Tokkyo Koho JP 88-41452 (1988) ; Tokyo Kasei Kogyo Co., Ltd., Eur. Pat. 218249 (1987)
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COVER STORY Addition of a functionalized lithium to an intermediate is unique, Harm says. In one step, the organolithium compound adds functionality and a carbon chain to the intermediate. Because functional groups on organolithium compounds usu ally are unstable, the transformation has not been readily available. Now, FMC Lithium is commercializing it, he says. Elsewhere, SNPE recently patented a method to prepare highly pure amino acid N-carboxyanhydrides (NCAs).Jean-Pierre Senet, scientific director for SNPE's fine chemicals group, says NCAs are polymer ized to peptides that serve as active ingre dients in pharmaceuticals or as delivery carriers in cosmetics. However, control of the degree ofpolymerization, which is key to these applications, is affected by impu rities in the monomers. According to the patent, NCAs are pre pared from amino acids by phosgenation in the presence of a chlorine scavenger. Thus, when L-leucine reacts with phos gene in the presence of α-pinene, the chlo rine in the product is less than 0.05%. aPinene forms bornyl chloride as it mops up the hydrochloric acid by-product. The
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chemistry is now practiced in 100-kg scale. As chemistries continue to be devel oped, technology for biopharmaceutical production also is being embraced more and more. Lonza's early entry into this are na is paying off in a big way Fine chemicals sales in 2001 were 30% higher than in 2000, mainly because of rapidly growing biotech sales, Edwards says. He adds that Lonza is investing $300 million to increase capacity for biopharmaceuticals. On the other hand, as a major produc er of baker's yéast, Kaneka has been in biotechnology for 50 years. And from that base, it has broken into fine chemicals, where it has focused on building expertise in asymmetric synthesis. Kaneka's fine chemicals group combines chemical synthesis and biotransformations to develop efficient processes that are keeping its capacity fully utilized, Walker says.
BRING IT ON Lonza's chemical/biocatalytic path challenges chemical route Sigma-Tau OH
CI^A^N1CH3)3 Quab ICyanation I Hydrolysis 0
OH
H 2 NA^A^N(CH 3 ) 3 Carnitinamide I Racemic separation I Hydrolysis
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- 0 A^Â^N(CH 3 ) 3 EFFICIENT PROCESSES are the key, Pollak says. Companies can't build on onestop shops, technology toolboxes, and customer intimacy without processes that cut the cost of a synthesis and the time to market of a product, he emphasizes. And in process development, companies committed to R&D lead. DSM'sfinechemicals business, for example, has 330 R&D people in seven sites worldwide, financed by 5% of its annual sales, according to Ellen de Brabander, global director of R&D for custom and multiclient chemical products. Collaborations with other R&D groups in DSM yield synergies resulting in successes. An example is DSM's route to cephalexin, now practiced in industrial scale. The route was codeveloped by DSM's anti-infectives group and fine chemicals group. It is based on using acylases to form an intermediate and the product. The reactions are water-based and generate less waste, making the process green, explains Marcel Wubbolts, competence manager for biocatalysis and biotransformations. He notes that other R&D synergies are evident in the fine chemicals group's use of the same enzymes in biocatalytic resolutions for making chiral amines and unnatural amino acids. At BASF, ChiPros products and services also take advantage of synergies in R&D, as well as in production and raw material use. The business, aimed at drug discovery and development, grew out of BASF's well-established expertise in amines and its more recently developed biotechnological capabilities. Although market research had identified chiral intermediates and services as a
L-Carnitine
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EVENTS HIGHLIGHT FINE CHEMICALS AUG. 4 - 9 , Drug Discovery Technology 2002. Boston. Contact IBC USA Conferences; (508) 616-5550; fax (508) 616-5522; e-mail:
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NOV. 4 - 6 , ChiraSource2002. Philadelphia. Contact Catalyst Group; (215) 628-4447; fax (215) 628-2267; e-mail: tcg@ catalystgrp.com.
SEPT. 8 - 1 2 , U t h International Symposium on Chirality. Hamburg, Germany. Contact Wilfried A. Kônig; 49 40 42838 2824; fax 49 40 42838 2893; e-mail:
[email protected].
NOV. 7 - 8 , CombiCat2002. Philadelphia. Contact Catalyst Group.
SEPT. 1 1 - 1 3 , FAST 2002,1st Forum on Asymmetric Synthesis & Technologies. Cambridge, England. Contact Nicole Lowery; 44 1642 553601; fax 44 1642 522542; e-mail: nicolejow ery@ici. com. SEPT. 1 6 - 1 7 , Large-Scale Chromatography, Symposium & Exhibition. Boston. Contact Scientific Update; 44 1435 873 062; fax 44 1435 872 734; e-mail:
[email protected].
NOV. 1 8 - 1 9 , Fine Chemicals Conference 2002. Amsterdam. Contact Morag Allward; 44 8708 730050; fax 44 8708 730051 ; e-mail:
[email protected]. FEB. 1 3 - 1 4 , 2 0 0 3 , Predicting Drug Metabolism. Venue to be announced. Contact Center for Business Intelligence Research; (800) 817-8601; fax (781) 939-2438; e-mail: cbireg® cbinet.com.
SEPT. 2 3 - 2 6 , 5 t h International Conference on the Scale-up of Chemical Processes. Prague. Contact Scientific Update.
FEB 2 5 - 2 6 , 2 0 0 3 , SPIE Microlithography 2003. Santa Clara, Calif. Contact SPIE, International Society for Optical Engineering; (360) 676-3290; fax (360) 647-1446; e-mail:
[email protected].
SEPT. 2 3 - 2 6 , 2 2 n d IFSCC (International Federation of Societies of Cosmetic Chemists) Congress. Edinburgh. Contact Peter Rand Group; 44 2476 237008; fax 44 2476 256264.
FEB. 2 5 - 2 8 , 2 0 0 3 , Informex 2003. New Orleans. Contact Synthetic Organic Chemical Manufacturers Association; (202) 721-4100; fax (202) 296-8120; http://www.informex.org.
OCT. 1-3, Conference on Pharmaceutical Ingredients. Paris. Contact CMP Information; 31 346 559444; fax 31 346 573811. OCT. K - 1 5 , Chiral USA 2002. Boston. Contact Scientific Update.
MARCH 2 - 5 , 2 0 0 3 , Catalysis in Modern Organic Synthesis. Cambridge, Mass. Contact ACS Prospectives; (800) 2275558 or (202) 872-4600; fax (202) 872-6013; e-mail:
[email protected].
OCT. 2 8 - 2 9 , Oxidation and Reduction: Potential Industrial Applications. London. Contact Scientific Update.
JUNE 4 - 5 , 2 0 0 3 , ChemSpec Europe 2003. Manchester. Contact DMG World Media; 44 1737 855073; fax 44 1737 855482.
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C & E N / JULY 2 2 , 2002
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COVER STORY BLENDED Kaneka combines chemical syntheses with biotransformations in antibiotic manufacture Microbial βhydroxylation
HOOC,
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to substrates. For example, chloroketone esters are reduced to chlorohydroxy esters in a two-phase system. Recently, Kaneka has been paying more attention to APIs. This year, an API it had been working on for several years was launched in Japan. The route to the prod uct—biapenem, an antibiotic—exempli
fies Kaneka's skill in combining chemical syntheses and biotransformations. Even though such combinations are be coming more and more common, they will not replace purely chemical routes. On this front, Pollak offers two exam ples: Finorga's process for an intermediate used in the synthesis of Pfizer's antide
pressant sertraline (Zoloft) and Roche's process for oseltamivir phosphate (Tamiflu), an antiflu drug. THE KEY INTERMEDIATE to sertraline is an aryl-substituted tetralone. Finorga, now a part of Dynamit-Nobel, used to make it through a demanding four-step synthesis from diethyl succinate, benzoyl chloride, and 0-dichlorobenzene. Aone-step process involving a Friedel-Crafts reaction between α-naphthol and 0-dichlorobenzene simpli fied production, enabling Finorga to become an important supplier of Pfizer, Pollak says. In the case of oseltamivir phosphate, Roche was under pressure to speed devel opment to try to win a race against Glaxo Wellcome, now GlaxoSmithKline, to bring an anti-influenza drug to market. The orig inal process involved 16 steps, required the expensive raw material (-)-quinic acid, in volved a hazardous azide intermediate, and gave poor yields, Pollak explains. The re sults of process development "are really fascinating," he says. First, Roche replaced the expensive raw material with the more readily available shikimic acid, eliminated the azide inter-
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COVER STORY mediate, cut the number of steps to 10, and raised yield from 10% to BREAKTHROUGH 35%. Then, a synthesis was develFinorga dramatically cut route to sertraline intermediate oped based on a Diels-Alder reaction between inexpensive raw maOld route terials, furan and ethyl acrylate. CH C0 CH CH Finally a third process, based on catAlCL alytic hydrogénation of a pyrogalS, lol, was designed. More recently Dow disclosed its manufacturing route for travoprost (Travatan), an antiglaucoma Pd/C agent [Org. Process Res. Dev., 6,138 (2002)}. The route was developed by a team led by Ian C. Lennon, technology leader at Chirotech New route Technology Ltd., nowpart ofDoVs pharmaceutical services business. Travoprost has five chiral centers and two stereochemically defined double bonds. Mindful of Aryl-substituted tetralone regulatory requirements for levels SOURCE: Peter Pollak of impurity, the team came up with a 22-step synthesis. Most of the steps go rification late in the route. From there, four many processes, there is much room for into assembling a single-enantiomer ke- steps complete the synthesis. improvement. But to be effective, it must tone that is then oxidized to a crystalline Process development is a paramount aim to reduce synthesis steps, switch to lactone. Formation of a crystalline product differentiating opportunity, Pollak says. It readily available raw materials, and simlimits the need for chromatographic pu- addresses a key need of customers, and for plify work-up. • 2
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