business
BIOCATALYSIS GROWS FOR DRUG SYNTHESIS Fine chemicals makers are increasingly using enzymatic methods to make chiral intermediates Michael McCoy C&EN Northeast News Bureau
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ever, Managing Director Alan Shaw says that biocatalysis is more and more becoming the economic way to impart chirality into complex molecules, provided that the requisite steep investment has been made in equipment and technology. "The biggest issue is the entry barrier," Shaw says. "At the end of the day, if a biotransformation works, it will usually deliver the most economic route." This, he adds, was definitely the case for (-)lactam, where both a chemical route and a racemate crystallization were also considered but dropped. Success with (-)lactam—as well as other chiral products based on both biocatalytic and classical syntheses—has kept ChiroTech sales doubling for each of the past three years. Its sales were $27 million in the fiscal year ended in February 1998, and Shaw expects them to double again this year. Not surprisingly, when Chiroscience decided to find an investor in ChiroTech, interest was high. Shaw says most of the world's major fine chemicals makers inquired about ChiroTech, because of its biocatalytic and other chiral chemical expertise.
ermentation and enzyme-based catalysis are starting to challenge traditional synthetic methods of producing optically active pharmaceutical intermediates. As these biocatalytic methods gain ground, a few organic chemistry-based intermediate manufacturers have climbed aboard, but not many open seats remain for the rest. Highlighting the growing importance of biocatalysis is Glaxo Wellcome's Ziagen (abacavir sulfate), an HIV (human immunodeficiency virus) treatment that was approved in mid-December 1998 by the Food & Drug Administration. Glaxo has contracted with outside manufacturers to make intermediates for the drug via two separate routes—both of which employ biocatalysis. ChiroTech, the chiral chemistry subsidiary of the U.K.'s Chiroscience Group, is producing (-)lactam, a key intermediate for abacavir, via a biocatalytic resolution in which racemic lactam is transformed by an acylase enzyme into (-)lactam and an amino acid. Glaxo, according to ChiroTech, has placed more than $40 million worth of orders for (-)lactam in anticipation of commercial launch of the drug. At the same time, Lonza, the Swiss fine chemicals maker and leading biocatalysis firm, has developed a process for an abacavir intermediate using a different approach. The imminent launch of a highprofile drug like Ziagen that uses biocatalysis in an important synthesis step shows that biocatalytic chemistry is becoming an increasingly important tool in the fine and custom chemicals manufacturer's toolbox. As a supplier of chiral intermediates, ChiroTech employs a number of synthetic methods, including asymmetric organic chemistry and classical Zeneea's large-scale fermentation racemate separation techniques. How- Bllllngham, England. 10 JANUARY 4, 1999 C&EN
capacity In
In the end, a 30% stake in ChiroTech was sold to the U.K. firm Ascot in September 1998 for $50 million. Ascot owns Mitchell Cotts Chemicals, the Yorkshire, England, fine chemicals maker where ChiroTech has contracted to have the bulk of its (-)lactam produced. Shaw likes the linking with Mitchell Cotts because it combines manufacturing scale and expertise with strong chiral technology. Still, he says, ChiroTech needs to do more to achieve critical mass in fine chemicals. "You need $150 million in sales to survive in this business," he says, noting that a complete joining of the two firms—combined with further acquisition—would be one route to that goal. "We have a ways to go, but are intent on doing it." Another company that recently linked biocatalysis with organic chemistry is Cambrex, an East Rutherford, N.J.-based pharmaceutical and fine chemicals firm, through its acquisition last January of the enzyme-based chiral intermediates business of Celgene Corp. John Stanulonis, president of the acquired business, now named Chiragene (based in Warren, N.J.), says the deal brought Cambrex new chemical and enzymatic routes to chiral intermediates and active pharmaceutical ingredients. Also, Chiragene now can use Cambrex facilities to scale up novel technology previously used only on a small scale. Stanulonis says the experience has been positive so far, and he expects Chiragene's sales to double in 1999, albeit from a small base. Among these sales will be commercial quantities of three intermediates, two of which are chirally active substituted aminotetralins, for drugs currently in clinical trials. Two of the intermediates are being made at Cambrex's Zeeland subsidiary in Zeeland, Mich., which Stanulonis also heads, and one at its Heico facility in Delaware Water Gap, Pa. Cambrex is carrying out further organic chemistry on the intermediates, illustrating, Stanulonis notes, the benefit of possessing a variety of synthetic techniques. As biocatalysts, the Chiragene technology primarily uses aldolase and transaminase enzymes contained in whole, nonliving cells that have been genetically engineered for improved performance. For the trial quantities, Cambrex is growing the cells on its own; Stanulonis says the company will add more fermentation
Biocatalysis harnesses power of enzymes
More elegant but more complex are whole-cell processes that serve the dual Known as biocatalysis, biotransforma racemic mixtures into their two optical purpose of introducing chirality and ad tion, or bioconversion, the use of bio ly active halves and those that yield vancing a multistep synthesis. Exam logical methods to produce pharmaceu asymmetric derivatives from racemic or ples include Zeneca's production of a tical products and intermediates comes prochiral precursors. Usually, enzymat chiral intermediate for Merck's antiglauic resolutions are performed with isolat coma drug dorzolamide, and NSC Tech in many forms. In the fine chemicals industry, bioca ed enzymes, whereas asymmetric syn nologies' production of L-phenylalanine talysis is generally thought of as a theses requiring the presence of cofac- for a number of products. Biotransformation's ability to intro means of producing optically active, or tors tend to use whole cells. Racemate resolutions based on isolat duce chirality is crucial in these cases, but chiral, small molecules that are either pharmaceutical products or intermedi ed enzymes are simple and proceed in others the approach is used to produce ates for pharmaceuticals. Larger mole much like reactions with traditional cat achiral molecules merely because classi cules such as antibiotics and therapeutic alysts. The drawbacks are that yields are cal chemistry would be difficult proteins are also produced biologically. often low, and the overall synthesis isn't One example is Lonza's ton-scale con version of 2,5-dimethylpyrazine to In small-molecule production, two advanced. Examples of enzymatic resolution in 5-methyl-2-pyrazinecarboxylic acid, an main types of biocatalysis are used: transformation of molecules inside the pharmaceutical industry include intermediate for the diabetes drug gli whole cells (which can be either alive or DSM Andeno's production of intermedi pizide, using a microorganism that dead) and conversion of molecules with ates for the heart drugs diltiazem and grows on p-xylene. In another case, isolated enzymes. Both processes use captopril, ChiroTech's production of a Lonza is producing 5-hydroxypyrazineenzymes: In one, the enzymes are left single-isomer form of the analgesic ibu- carboxylic acid in a single microorgan inside the cells, and, in the other, they profen and (-)lactam for the HIV drug ism that carries out two chemical steps. abacavir, and BASF's production of opti This compound is an intermediate for a are separated and often purified. These enzymatic reactions fall into cally active amines using a lipase en tuberculosis drug currendy in clinical trials. two broad categories: those that resolve zyme in organic solvents.
capacity or partner with an outside fer mentation firm if the drugs are approved and larger quantities are needed. A desire to avoid relying on outside companies for biocatalysts is one of the reasons that DSM, the company that con siders itself the world leader in biocataly sis for fine chemicals, last year acquired fellow Dutch company Gist-Brocades, a producer of antibiotics, enzymes, bakery yeasts, and food specialties. Emmo Meijer, president of DSM Re search, says even before the acquisition, DSM had some $250 million in annual sales of products based on what DSM calls biotransformation—the use of en zymes or dead-cell preparations to carry out chemical reactions. Now, with GistBrocades aboard, that figure is in the neighborhood of $500 million. Much of this business is in nonpharmaceutical fields, such as the enzymatic production of the sweetener aspartame, or in the antibiotic sector, such as the enzymatically produced ^hydroxyphenylglycine "side chain" for the antibiotic amoxicillin. DSM's business in intermediates for pharmaceutical industry customers lies mostly in the Andeno unit of its DSM Fine Chemicals group. Meijer says annual sales are $150 million, about 30% of which are products made via biotransformation. These include intermediates for cardiovas cular drugs such as the calcium channel blocker diltiazem and the ACE inhibitor
captopril. The active ingredients of bothι I portunities still exist—Monsanto's NSC drugs are made with an enzymatic resoluh Technologies and Zeneca's LifeScience tion as a key intermediate step. Molecules (LSM) unit. Despite this strong presence in enιFollowing its aborted merger with zyme-based chemistry, Meijer says DSMI American Home Products last year, Monpreviously had to try to interest enzymes santo announced plans to pare down to manufacturers in developing appropriateî a select group of core businesses and enenzymes to do the job. "Enzyme makerss tertain offers for everything else, aren't interested in a lot of developmentt One of those noncore businesses is work with an uncertain outcome," heî Mount Prospect, Ill.-based NSC, a supplisays. As a result, the company often hadi erof chiral intermediates, many of which to work with already available enzymes.i. have grown out of work done by the Now, through Gist-Brocades, DSM has s R&D organization of Monsanto's Nutrain-house enzyme production capabilityγ Sweet unit on its whole-cell microbial and also is able to engineer organisms to) fermentation route to the amino acid Lproduce new enzymes with propertiess phenylalanine. NutraSweet's aspartame not expressed in nature. "With new de:- sweetener is composed of L-phenylalavelopments in molecular biology, we ares nine and L-aspartic acid. able to teach microorganisms new7 Michael Altman, NSC's director of tricks," Meijer says. marketing, says many but not all of the He says new enzymes are just one ex:- company's products are made by comample of the "enormous" interactions inl bining the fermentation-derived L-phenylbiocatalyst development and metabolic: alanine with further chemical or enzypathway engineering that are emergingl matic synthesis steps. Altman says these between the "old" DSM's fine chemicalss products, generally custom produced, business and Gist-Brocades' enzyme and1 are intermediates for a number of curantibiotic businesses. "It's the same techL- rent and in-development pharmaceutinology base," he says. "If we hadn'tt cals, such as protease inhibitors, ACE inmerged, we would have had to develop5 hibitors, and diabetes treatments. it ourselves." In June of last year, NSC announced For fine chemicals makers seeking toD the multi-ton-scale production of two gain biocatalytic capability, ChiroTech,., other amino acids—D-phenylalanine and Chiragene, and Gist-Brocades are threeζ D-tryrosine—that, like L-phenylalanine, names that are now off a limited list off are "platforms" for a series of derivative potential acquisitions. However, forr products that have use in HIV treatment, those with deep pockets, two choice op-\- I oncology, and cardiovascular drugs. JANUARY 4, 1999 C&EN 11
business The new products are produced by Darnino acid transaminase enzymes found in bacteria that have been enhanced by genetic modification. In the future, Altman says, NSC will commercialize more unnatural amino acids through the devel opment of "designer enzymes" within microorganisms. NSC expects to reach $80 million in sales for 1998, continuing an annual dou bling of sales that started in 1995. As was the case with ChiroTech, industry ob servers say that interest in NSC is high among the big fine chemicals players. One observer says the bidding for the business is approaching $200 million, de spite the fact that much of its production is carried out either in Monsanto or in toll manufacturer facilities. Zeneca LSM—generally considered one of the top three players in biocatalysis, along with DSM and Lonza—is an even more expensive proposition, be cause it's embedded in the $1.5 billion Zeneca specialty chemicals business, which Zeneca put up for sale in Novem ber 1998, prior to its announced merger with Sweden's Astra. Zeneca LSM had sales in 1997 of $92 million, and according to Kevin Tay lor, general manager for Zeneca's North America operations, 1998 sales should be close to $120 million. Roughly a quarter of the business, he says, is in products made via biocatalysis, with the rest in or-
ganic synthesis, and peptide and oligonuι- Ι company has contracted with an undis closed third party to produce commercleotide chemistry. Zeneca has had a number of biocataL- cial quantities of the atorvastatin intermelytic successes, Taylor says, including aι diate via the fermentation route that Zenmicrobial fermentation used to make thet eca developed. active ingredient in Merck & Co.'s Tru-ιTaylor echoes other fine chemicals sopt antiglaucoma drug. Part of a Zeneca-ι- executives in noting that success in supdeveloped multistep synthesis, the bio-H plying drug intermediates and active intransforming portion uses a fungus to) gredients requires a broad synthetic platconvert a ketosulfone into a hydroxysul-l- form, of which biocatalysis is just one fone, introducing a chiral center in thet piece. process. The manufacture of a modern pharZeneca also used biocatalysis in ai maceutical active ingredient is a lengthy route it developed on behalf of Warner-- process often involving 10 or more synLambert for a key intermediate for ator-- thetic steps. Even in compounds that are vastatin, the active ingredient in thet made with biocatalysis, generally just firm's $1 billion anticholesterol drug Lipι- one of these steps will be biocatalytic, itor, introduced in 1997. Taylor notes, although it is often the key Taylor says the long-term cost of theι step that introduces chirality into the fermentation route was about equal to) compound. Nevertheless, because of the increasthat of a competing low-temperature synιthetic method. In the end, however,, ing prominence of chiral molecules, he Warner-Lambert decided to launch theι sees biotransformation growing faster drug with the synthetic route because itt than other synthetic methods, and even was further along in development and1 growing faster than other chiral methods less capital intensive at the time. as the number of chiral centers grows, "The general view is that asymmetric According to Taylor, developments att Zeneca within just the past couple off chemistry is the best route to comyears might tip the scale in favor of theι pounds with single chiral centers," Taybiocatalytic approach. "If we were att lor says. "But compounds with multiple that point today, we could make a betterr chiral centers start to favor a biocatalytic case for the bio route," he says. route." DSM's Meijer is similarly bullish. He Indeed, although Warner-Lambertt wouldn't comment, other industry sourc:- notes that the makeup of today's drug es say that since the drug's launch, theι I pipeline suggests that in the future as
For DSM, antibiotic and fine chemi cals production are separate businesses, In a similar move, DSM recently said its but DSM Research President Emmo Mei Fine chemicals industry executives con sider the production of penicillin and anti-infectives group, part of the former jer notes that there are strong synergies other fermentation-derived antibiotics to Gist-Brocades, would spend $130 million between the two segments. For exam be a different business than biocatalytic to build a plant that will make 7-ami- ple, he says, DSM plans to use its com synthesis, but advances in recent years in nodesacetoxycephalosporanic acid (7- bined resources to develop biocatalytic the semisynthetic antibiotic realm are ADCA) via a fermentation route (C&EN, routes to other antibiotics now pro- | Dec. 7, 1998, page 24). 7-ADCA is a pre duced chemically and to newly devel based on many of the same techniques. Producers of cephalosporin antibiotics cursor to other cephalosporin products oped fine chemicals. Likewise, Ermanno Bernasconi, head • traditionally have made natural cephalo such as cephalexin and cefadroxyL As is the case for Antibioticos, the DSM of R&D at Antibioticos, says his firm is I sporin C by fermentation, then chemically modified it to yield 7-aminocephalospor- facility will biocatalyticaUy produce a using new microorganism optimization anic acid (7-ACA), the precursor to semi cephalosporin precursor that is now techniques such as recombinant DNA synthetic cephalosporins such as cefazo- made by a chemical route; for 7-ADCA, technology and metabolic engineering ; to broaden the utility of fermentation j the starting material is penicillin. lin, cefotaxime, and cefuroxime axetiL DSM's use of biocatalysis in antibiotic and enzyme catalysis. However, since 1994, the Italian anti Antibioticos is already using fermen- | biotics producer Antibioticos, part of production continues downstream. The the Montedison Group, has been per so-called semisynthetic cephalosporins tation to produce an anthracycline-class ! forming the conversion of cephalospor are generally made by a chemical reac anticancer drug and an immunosupprein C to 7-ACA via an enzymatic route at tion of 7-ACA or 7-ADCA—dubbed the sant that helps prevent the rejection of its facility near Turin. The company, the "nucleus"—with a "side chain" mole transplanted organs, both for multina world's largest 7-ACA producer, still cule, but DSM, through its Chemferm tional pharmaceutical firms. Bernasco- ' makes the intermediate via the old subsidiary, does this with an enzymatic ni says the company intends to further ; chemical route as well, but it is investing reaction. DSM Fine Chemicals' Deretil apply biocatalysis to pharmaceuticals ; in a second enzymatic facility that could unit produces some of the side chain and food supplements, for itself and ! other firms. molecules enzymatically as well. replace the chemical-route plant.
Antibiotic makers learn new tricks
12 JANUARY 4, 1999 C&EN
Enzymatic resolution is key in diitiazem synthesis Enzyme t
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without biocatalytic ability—and that group includes most of the U.S.-based in dustry—are actively investigating how to gain it, and soon. Paul D. Taylor, vice president of tech nology for International Specialty Prod ucts' fine chemicals unit, believes that a good part of the future of fine chemicals
manufacturing lies in biocatalysis. "There are two practical procedures for making intermediates with optically active cen ters: through organic synthesis and with biocatalysis," he says. "ISP Fine Chemicals currently does the first, and we need to be in biocatalysis as well." The big players in biocatalysis have had years to develop their expertise and production capacity, and Taylor ac knowledges that it would be difficult for a company to duplicate such an effort inhouse. As a result, ISP is surveying the landscape for acquisition opportunities, but Taylor admits that the choices are few and expensive. The company's answer to a similar need for capacity in organic synthesis last year was to acquire a fine chenrxals plant from Polaroid Corp. in Freetown, Mass., then launch an effort to upgrade it to pharmaceutical intermediate stan dards. Taylor says a novel approach like this may be necessary in biocatalysis as well. Merck & Co., the world's largest phar maceutical producer, is the kind of cus tomer that any fine chemicals maker
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CIRCLE 2 ON READER SERVICE CARD
JANUARY 4, 1999 C&EN 1 3
business of the strength of our company, we can walk awayfroma deal [that does not look good]." It would seem, however, that the companies' managers failed to gauge accurately the reaction among shareholders. "It really was a very unpopular thing here. No one could see the point of it," the Zurichfinancialexpert says. "That is not a good sign. But the sour reaction among shareholders probably was influential" in convincing the companies finally to withdraw from the deal. Some securities analysts believed the deal was a good one. For example, New York City-based Paine Webber analysts said it would be "a very powerful combination." And London-based Morgan Stanley Dean Witter analysts termed the merger "a unique and exciting event in the world of specialty chemicals. The strategic rationale for the merger appears strong." However, it seems that that outlook was not shared by Ciba and Clariant shareholders. The stock prices of the two companies jumped on Nov. 10, the day following the merger announcement. From that point on, however, they began drifting downward. "Had the managers stood up when the shares went down and said: 'We have very good reasons [for the merger],' people The Swiss have a reputation for doing ership of a significant block of Clariant might have said, 'Well, okay, we can see your reasoning,' " says the Zurich financial things quiedy and efficiently. Swiss trains complicated the antitrust picture. run on time—nearly always. Swiss orgaTlie two companies say the deal was expert, who asks not to be identified. "But nization runs smoothly—nearly always. called off after a period of extensive due not to have done that—it certainly won't So one almost gets the feeling of patri- diligence indicated that the commercial, fi- do the people who put the decision tootic pique in Zurich, thefinancialheart of nancial, legal, and regulatory risks and con- gether any good for their reputations." The original deal was hatched by Ciba Switzerland, over Clariant and Ciba Spe- straints in putting the deal together were cialty Chemicals' mid-December decision just too high to make it pay. "Both sides Chairman Rolf A. Meyer and Clariant to call off the merger they had announced have the courage to say it was not going to Chairman Rolf W. Schweizer. Schweizer with great fanfare on Nov. 9, 1998. As work," one Ciba executive says. "Because would have taken over as chairman of the new company and Meyer much as the firms see it —•———^~ as chief executive officer. as a "courageous" deci^^~^^~ No mention was made at sion to call off something Stocks wereffaNbigas merger was debated the time of the two curthey decided wouldn't suit Ciba stock, Swiss francs Clariant stock. Swiss francs rent CEOs, Hermann Vodeither party,financialob^Merger - ^ 1800 1501 Merger icka at Ciba and Karl-Gerservers see it as plain and . canceled announced. 780 hard Seifert at Clariant, simple bungling. both highly respected exOne Zurich financial ecutives on the European observer says, "Everyone chemical industry scene. was astonished" when Subsequent elaboration the merger was canceled. of the merger proposal "They mucked things up confirmed that the two royally. They didn't seem would be let go. really to have done their homework." Vodicka subsequendy has resigned from Ciba, For example, when effective the beginning the deal was canceled it of this month. Seifert, was still unclear whethhowever, will continue er it could have gone at Clariant. through in the U.S., Patricia Layman where the Hoechst ownwould like to serve with the right synthesis capabilities. And the view from Merck is that biocatalysis will grow in importance in the coming years. Barry Buckland, vice president of bioprocess R&D at Merck, notes that his company's policy has long been to develop the correct enantiomer, when possible. "We don't go forward with racemates," he says, "and that opens up the opportunity for applying enzymes because of their ability to make the desired enantiomer." Buckland says Merck's general approach to synthesis is to try chemistry first. "If there's a straightforward chemical solution, then our group doesn't get involved," he says. "But if there are steps that are difficult synthetically, then we will evaluate the biocatalytic approach." In the longer term, Buckland says Merck is interested in metabolic engineering of cells to produce advanced intermediates—in effect, replacing several chemical synthesis steps with one fermentative transformation. For example, Merck scientists are col-
laborating with Massachusetts Institute of Technology's biology department on a fermentation route to its Crixivan antiHIV drug. The active ingredient in Crixivan, indinavir sulfate, is a complex molecule with five chiral centers that is now produced by an expensive multistep chemical process. The goal of the collaboration is to metabolically engineer a microorganism to convert indene, a commercially available compound, into cis aminoindanol, a precursor to Crixivan that contains two of the chiral centers. DSM Andeno has disclosed that it is Merck's current supplier of this intermediate. If successful, however, the new approach would use one biotransformation rather than the multiple chemical synthetic steps that DSM now employs. Buckland cautions that the work is strictly exploratory, but he says he is excited about the opportunities that lie in advanced bioprocessing like this. "The whole area of molecular biology is expanding at an incredible rate," he says. "The likelihood of success is improving year by year as the science improves."^
Ciba-Clariant merger: 'Courage' or bungle?
14 JANUARY 4, 1999 C&EN
