science/technology
Fine chemicals firms that supply this market show off new chiral intermediates, .gi catalysts, reactions
H \\\ih mmuit^ Stephen C. Stinson C&EN Northeast News Bureau
T
he chiral drug industry soared through a major milestone last year, as annual sales in this rapidly growing segment of the drug market topped $100 billion for the first time. These compounds now represent close to one-third of all drug sales worldwide. The industry's continuing growth is rooted, in part, in fundamental biochemistry. The biological messenger molecules and cell surface receptors that medicinal chemists try to affect are chiral, so drug molecules must match their asymmetry. A second reason for the sector's growth arises from the continuing concern of the Food & Drug Administration that companies make appropriate choices about whether to develop inherently chiral drug molecules in their singleisomer or racemate forms. The logistics of testing are simpler for a single isomer because FDA requires that both enantiomers of a racemate be studied in detail. Against this backdrop of growing
markets, the drug industry and its fine chemicals suppliers will gather next month for the Conference on Pharmaceutical Ingredients (CPhI) in Milan, Italy. There, drugmakers will find that, despite intense involvement in mergers and acquisitions, fine chemicals suppliers have many new products to offer them. Single-isomer drug sales reached $115 billion worldwide in 1999, up 16% from $99 billion in 1998, according to Richard L. DiCicco, president of the consulting firm Technology Catalysts International Corp. (TCI), Falls Church, Va. He estimates that this class will grow at an average annual rate of 8% to $146 billion in 2003. Single-isomer drugs accounted for 30% of the $335 billion total drug sales worldwide in 1998, edging up to 32% of the $360 billion market in 1999. Drug companies are also using chirality as a tool either to extend the patent lives of their blockbuster drugs or to increase their "status," DiCicco notes. A blockbuster is a drug with more than $1 billion per year in sales.
But in this upbeat atmosphere for chiral drugs, DiCicco notes a disturbing number of promising single-isomer blockbuster candidates that have either stumbled or failed this year. These setbacks have been troubling not only to the drug company innovators but also to the fine chemicals producers who had shared the risk of developing the drugs.
Racemic switching One example of the use of chirality to extend patent protection and so manage a product's life cycle is AstraZeneca's plans for its Prilosec brand of omeprazole antiulcer drug. AstraZeneca has redeveloped a single-enantiomer form of the drug that it had previously been been marketing as a racemate. AstraZeneca of London, England, and Wayne, Pa., has marketed racemic omeprazole in the U.S. since its approval here in 1995. But the pharmacological activity resides in the (S)-enantiomer, and the patent on the racemate runs out in 2002. So AstraZeneca will make a racemic switch: The company has patented the (S)-isomer separately, which is OCTOBER 23, 2000 C&EN 5 5
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science/technology
value of sales in 2002 known by its own generic comes from the lower pricname esomeprazole. AstraChiral drug sales hurtle past es charged by generic Zeneca's Nexium brand of $100 billion and show no sign of slowing producers. esomeprazole was apGlobal sales But AstraZeneca will proved for marketing in Eu2003 1999 1998 $ Millions start reaping sales of rope in July, and the com$50 million from esomeprapany expects approval in $26,012 $24,805 Cardiovascular $21,906 zole in 2000, $200 million in 23,265 the U.S. later this year. 20,907 19,756 Antibiotics/antifungals 2001, $400 million in 2002, 17,345 13,760 12,297 Omeprazole is a proton Hormones/endocrinology and $750 million in 2003, 13,360 9,420 Cancer 8,006 pump inhibitor, which DiCicco estimates. 13,720 8,592 7,027 Central nervous system means that it prevents se11,445 8,580 6,730 Hematology All these estimates concretion of gastric acid. Be13,446 7,540 6,131 Antiviral tain two wild cards, howevcause many ulcers result er. One is how AstraZeneca from a local infection by 8,795 5,087 4,305 Respiratory will price single-enantithe bacterium Helicobacter Gastrointestinal 5,355 2,998 1,718 omer Nexium. The second pylori, omeprazole is often 2,070 1,794 1,482 Ophthalmic is how ulcer patients will prescribed in combination 1,540 1,270 1,124 Dermatological use the drugs. Pricing is with such antibiotics as cla1,135 1,045 842 Analgesics complicated by the fact that rithramycin and amoxicil1,100 676 Vaccines 568 a 20-mg tablet of single-iso7,425 8,527 lin. The antibiotics eradi7,947 Other mer esomeprazole contains cate the infection, and ome$146,013 $115,001 TOTAL $99,389 the same amount of active prazole halts acid secretion ingredient as a 40-mg tablet Source: Technology Catalysts International Corp. to promote healing. of racemic omeprazole. DiCicco estimates U.S. Many drug marketers besales of omeprazole in 1999 lieve that the single enantiomer should at $5.9 billion. He expects sales to rise get $2 billion of the drug's market, he to $7 billion in 2000 and $8 billion in says, while AstraZeneca's sales fall to be priced at a slight discount compared 2001. In 2002, generic producers may $3.1 billion. The decrease in the total with omeprazole to encourage doctors
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to change patients' prescriptions to Nexium, particularly when faced with the option of a lower priced generic racemate competitor. The issue of patient behavior is com plex. In order to gauge these effects, as well as doctors' prescribing patterns and to analyze results of clinical trials on sales estimates, DiCicco has begun hir ing a panel of physicians that he calls his clinical research analysis group. Physi cians working on the TCI staff so far are cardiologist Cathy Groupe, oncologist Wendy L. Schulman, and gastroenterologist Shaw Jones. Analysts Natalie Dearing and Francine Rosenberg work with them to gather data about clinical trials. Jones has already alerted DiCicco to the subtle effects on sales of ulcer drugs as a result of the behavior of uninsured patients. These patients may delay tak ing any drug until ulcer pain becomes severe, he says. They may also cut pills in half to stretch out a prescription. The behavior of insured patients can have an impact, too, particularly if the generic form of a drug is sold as an overthe-counter product. Third-party payers such as insurance companies usually will not reimburse patients for over-thecounter drugs, although they will pay for a prescription version. Thus, insured patients may ask a doctor for a prescrip tion, even when a cheaper over-thecounter product is available. Another issue affecting sales of pat ented chiral drugs like omeprazole and esomeprazole is what is called the "eco nomic credentialing" of doctors by health maintenance organizations (HMOs). Doctors who prescribe larger average amounts of these costly drugs than their peers receive "letters" from HMOs and have difficulty with "recredentialing." Companies like AstraZeneca that de velop their own drugs are not the only ones taking advantage of the benefits of switching from racemic to single-isomer forms of chiral drugs. Sepracor of Marl borough, Mass., has been switching the drugs of other companies for years. When Sepracor discovers that the phar macological activity of another compa ny's racemic drug resides in just one enantiomer, thefirmpatents that isomer if the innovator company has not already done so. Sepracor is ready to license back the innovator's single-isomer drug but is prepared to go ahead with market ing on its own part if the innovator does not take a license.
For example, Sepracor found that the antidepressant activity of fluoxetine, marketed by Eli Lilly, Indianapolis, as Prozac, is in the (S)-enantiomer. Sepra cor patented (S)-fluoxetine in January 1998 and proceeded with clinical trials. In 1998, Lilly took a license on Sepracor's patent, agreeing to pay a $20 mil lion license fee and $70 million in mile stone payments as (S) -fluoxetine wends its way through FDA's new drug approv al process. Lilly will also pay royalties on sales for years after approval.
But Schering Corp., Kenilworth, Ν J., is hanging tough on the levorotatory isomer of its racemic bronchodilator inhalant, albuterol, which it sells under the brand name Proventil to treat asthma. Sepracor patented and went ahead with clinical trials of levalbuterol, got FDA approval in March 1999, and began marketing to aller gists, general practitioners, and respi ratory physicians under the brand name Xopenex. Since Schering decid ed not to take a license, Sepracor li-
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censed Abbott Laboratories, North Chicago, 111., in November 1999 to market Xopenex to pediatricians. Sepracor is working on scale-up procedures for other chiral drugs as well. Principal chemist Kevin Fang de scribed commercial-scale production of (S)-bupropion at the American Chemical Society meeting in Washing ton, D.C., in August. Glaxo Wellcome, Research Triangle Park, N.C., discov ered the racemate and markets it un der the trade name Wellbutrin for depression. At the August ACS meeting, another Sepracor principal chemist, Yaping Hong, talked about a commercial route to (S)-desmethylzopiclone. RhônePoulenc Rorer, Collegeville, Pa., discovered racemic zopiclone and sells it in Europe as a sleeping pill under the trade names Imovane and Amoban. Desmethylzopiclone is a metabolite of zopiclone in which an N-methyl piperazine has been demethylated. There is much recent interest in metabolites of known drugs as well as in their enantiomers as potential drugs themseves. This is because drugs can compete with one another for the same enzyme to metabolize them. Such competition can lead to unfavorable drug interactions if the one drug ties up the available enzyme and the other drug builds up to excess blood levels. Fang reported that Sepracor's technology for (S)-bupropion begins with m-chloropropiophenone. The company converts that to a silyl enol, which undergoes asymmetric dihydroxylation to (J?>m-chloro-p-hydroxypropiophenone. The trifluoromethanesulfonate ester of that intermediate undergoes displacement by teri-butylamine TCI's clinical research analysis group (from left) Dearing, Groupe, Sculman, Rosenberg, DiCicco, and Jones.
58
OCTOBER 23, 2000 C&EN
to yield (S)-bupropion. Fang also reported a commercial synthesis of single-enantiomer (S) -hydroxybupropion metabolite. Hong described two methods for making (S)-desmethylzopiclone on a large scale. In one method, the company uses D-malic acid to resolve zopiclone by classical diastereoisomeric crystallization to the (S)-isomer, which is demethylated with 1-chloroethyl chloroformate. In the second method, racemic desmethylzopiclone, made by demethylation of zopiclone or other syntheses, is resolved with Nbenzyloxycarbonyl-L-phenylalanine. Sepracor's experiences with zopiclone and desmethylzopiclone point out a salient feature of modern production of single-enantiomer drugs: Classical diastereoisomeric crystallization of salts with resolving agents is still the most prevalent method of separating enantiomers. Sepracor announced in September that it is in Phase III clinical testing of (S)-zopiclone in the U.S. Phase III is
the final, large-scale test of a drug on humans before approval to market.
Marketing drug combinations In addition to extending patent protection on a racemic drug by later patenting its single active enantiomer, drug companies can "enhance its status," as DiCicco puts it, by combining an old drug with a newer, patented one that treats the same disease condition but by a different mechanism. For example, Whitehouse Station, NJ.-based Merck markets a combination of Merck's simvastatin and Schering's ezetimibe, both single enantiomers, to lower serum cholesterol. Simvastatin inhibits the enzyme p-hydroxy-p-methylglutarylcoenzyme A reductase, which mediates a step in the biosynthesis of cholesterol, while ezetimibe inhibits the absorption of dietary cholesterol. A second example of enhancing an older single-enantiomer drug is the marketing by Schering of a combination of Merck's montelukast with Schering's loratidine for asthma. Both
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>95% ee ee = enantiomeric excess
The company's key catalyst is a diphosphino ferrocene. Lonza recently demonstrated its enantioselective prowess in both hydrogénation and hydroamination. In a process to make piperazinecarboxylic acids, for example, the company begins with partial hydrogénation of methyl 2-pyrazinecarboxylate to the A2-tetrahydro derivative. After further transformations of that to the A^N'-diacetyl fe/tf-butylamide, Lonza hydrogenates asymmetrically with a rhodium-ligand catalyst to get the protected (S)-piperazine acid in 95% ee. The same ligand functions with iridium® to catalyze asymmetric hydroamination. For example, reaction of norbornene with aniline yields (2S)-exophenylaminonorbornane in 92% ee. Among capabilities at ISP, Wayne, N.J., are reactions at low temperature. Paul D. Taylor, vice president for technical development and quality assurance, says that the company has a total 6,850 gal of low-temperature reactor capacity. The largest vessel is 3,500 gal, cooled by direct injection of liquid nitrogen into the jacket coils. Direct injection means
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science/technology the company can theoretically achieve -160 ° C, and Taylor says they have actually been down to -110 C°. He points out that such low temperatures are really cost-effective once a company has made the initial investment to install the capacity. The reason for going to such low temperatures is usually not to control exotherms of highly reactive chemicals, Taylor notes, but to achieve high enantioselectivity. He cites the example of one project to make tert-b\xty\ (S,S)-p,6-dihydroxycaproate. The key step was reduction of (S)-ô-hydroxy-p-ketocaproate with sodium borohydride. In order to ensure asymmetric induction from the (S)-hydroxyl group, ISP chemists added triethylborane. The borane formed a six-membered ring complex with the keto and hydroxyl oxygen atoms, holding the molecule rigid for approach of the hydride reductant. But the complex was only stable at -80 °C. Warming even to -60 °C began to degrade the complex. Other capabilities of ISP are Grignard reactions and boronic acid produc-
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science/technology tion. Boronic acids are useful in the Suzuki coupling reaction, in which the acid couples with an aryl or alkenyl halide. The company makes them by lithiating aromatic compounds and treating the organolithiums with triisopropyl borate. It comes by its Grignard expertise from the longstanding production of insect pheromones at its plant in Columbus, Ohio. In addition to its Columbus plant, which operates under FDA's current good manufacturing practices (cGMP) regulations, ISP has a plant in Freetown, Mass., that it is bringing up to cGMP. Taylor says the Freetown plant will produce itsfirstbulk active drug in the first quarter of 2001. Like Onyx Scientific, Johnson Matthey, West Deptford, N.J., got an entrée into enantioselective chemistry by licensing academic technology. The company licensed the patents for asymmetric diazo chemistry invented by Michael P. Doyle, an organic chemistry professor at the University of Arizona, Tucson. The reactions covered include cyclo-
MSU's Hollingsworth: carbohydrates have abundant chirality
propanations and insertion into carbonhydrogen bonds. The catalysts consist of two rhodium (I) ions complexed by four molecules of enantiomeric fivemembered heterocyclic carboxylates.
R1AOY lftADÉ. FOR" SUCCESS:
A recent application of the Doyle catalysts is that of organic chemistry professor Stephen F. Martin of the University of Texas, Austin. Martin makes a phenylcyclopropanated butyrolactone in which the phenyl group is trans to the lactone carbon atoms. This product can then be converted to a diaminophenylcyclopropane that has the right stereochemistry to fit into a peptide as an analog of an enkephalin. In particular, internal cyclization of transcinnamyl diazoacetate with a Doyle catalyst using (S)-pyroglutamic acid as a ligand gives the product with the needed stereochemistry. Rather than license technology off the shelf, Dow Contract Manufacturing Services (CMS), Midland, Mich., has reached out to industrial and academic partners to develop proprietary enantioselective technology. Two recent agreements are with the Center for Applied Catalysis at Seton Hall University, South Orange, N.J., and Diazem Corp., Midland, Mich. The agreement with Seton Hall is to develop heterogeneous asymmetric catalysts. Diazem will invent pro-
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science/technology prietary, enantioselective, liqatoms to 12 outer tungsten at uid-chromatographic columnoms. The heteropoly acid Intramolecular cyclopropanation packing material. binds to the outer surfaces of The virtue of heteroge the clay particles, and the CfiHc CfiHj neous catalysts is that they are asymmetrically chelated rho insoluble in reaction mixtures, dium ions become part of the HVV'H Rh2-ligand and the user can filter them outer tungstic acid structure. off. Robert L. Augustine, catal The Seton Hall workers dem ysis center executive director onstrate the heterogeneous and emeritus organic chemis catalyst by hydrogenating using Doyle catalyst. try professor, explained the α-acetamidoacrylic acid to NSeton Hall approach to the acetyl-L-alanine in 92% ee. Chiral USA 2000 conference Rhodium does not leach from c 2 CH 3 *C0 H in Boston last May. The heart the catalyst on reuse, and the of the approach is to incorpo enantioselectivity of the Ligand rate homogeneous catalysts product actually increases into an insoluble support with reuse. leads t o enkephalin analogs substance. Diazem's technology for CcHi '6 n 5 chiral and other liquid chro In one version, the investi C0 2 CH 3 matography column packings gators use montmorillonite comes from 12 patents that clay as the solid support. They H II H H the company licenses from treat a stirred methanol slurry Dow Corning, Midland, Mich. of the alkaline clay first with Tyr = tyrosine The key step is the reaction of phosphotungstic acid, then specially treated silica gel with with a chelate of rhodium (I) fluoborate with cyclooctadiene and no]ethane. Phosphotungstic acid is a 3-aminopropyltrimethoxysilane, which DIPAMP, which is (i?,i?)-(-)-l,2-bis- complex of a central phosphorus atom binds 3-aminopropyl groups covalently [ (0-methoxyphenyl) (phenyl) phosphi- linked through a network of 52 oxygen to the silanol surfaces in the interiors of
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