COVER STORY
CHIRAL CHROMATOGRAPHY Simulated moving bed installation at CarboGen subsidiary of Solutia, Aarau, Switzerland, separates U kg of racemate per day.
CHIRAL CHEMISTRY Driven by the needs of the drug industry and fueled by the ingenuity of chemists, sales of single-enantiomer chiral compounds keep accelerating STEPHEN C. STINSON, C&EN NORTHEAST NEWS BUREAU
w
O R L D W I D E , THE MARKET FOR CHIRAL FINE
chemicals sold as single enantiomers was $6.63 billion in 2000 and will grow at 13.2% annually to $16.0 billion in 2007, according to a study by the market research firm of Frost &
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Sullivan, London. The drug industry is the engine that is driving this strong growth, according to senior industry analyst David Piatt, accounting for 81.2% of the total, or $538 billion worth. The remaining $1.25 billion is divided among such uses as agricultural chemicals, electronics chemicals, and flavors and fragrances. By geography, the U.S. is the biggest consumer of enantiomeric fine chemicals, C&EN
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COVER STORY Piatt says, contributing to a total North American share of $3.98 billion, or 60.0% of the total. European and Asian consumption of enantiomeric fine chemicals isn't expected to grow as fast, with the North American share rising to 66.9% of the market in 2007, or $10.7 billion.
atorvastatin from Pfizer, New \ b r k City; cerivastatin from Bayer, West Haven, Conn.; and simvastatin from Merck. The drug industry will continue to spur strong growth in chiral compounds, according to Erb and Zhou, because of efforts to improve drug efficacy and to cut development costs in the face of regulatory pressures. Medicinal chemists increasingly target enzymes, hormones, and other compounds in patients' cells and in cells of microorganisms. Additional targets are receptors on cell surfaces. These compounds and receptors are made up of chiral amino acids, carbohydrates, and lipids. Drugs that are intended to interact with them must be enantiomeric for increased chances of success. On the regulatory front, the enantiomer-racemate interface is important either for simplicity of development or for life-cycle management of drugs. Erb and Zhou say it is simpler to choose one enantiomer and to develop that rather than to build evidence about a racemate, which from a regulatory point ofview is like developing two different drugs. But some drug companies patent and develop a racemic drug with the intention
of patenting and developing a single enantiomer later. When the patent on the racemate expires, Erb and Zhou point out, the company can undercut generic competition by launching the single enantiomer.
IN THIS CLIMATE ofyeasty growth for single-isomer chiral compounds, producers THE NUMBERS look even more impresof fine chemicals are honing their enansive when considered as the sale of singletioselective technologies. These producenantiomer compounds made into the ers realize that their customers will want pharmaceutical formulations that people syntheses of increasingly complex moleactually consume. The worldwide market cules. Also, there is a desire for new for dosage forms of single-enantiomer chemistries to improve manufacturing effidrugs was $123 billion in 2000, up 7.2% ciency and to establish or get around from $115 billion in 1999, according to patented technologies of others. data developed by Technology Catalysts In addition to their in-house research, International, Falls Church, Va. Sandra E. some fine chemicals companies have allied Erb, who is manager of chiral and finethemselves with academic chemists to chemicals consulting, and senior research expand their portfolios. Entrepreneurial associate Jane Zhou point to respiratory, university faculty members have also gastrointestinal, ophthalmic, and cardiofounded their own companies and feed vascular drugs as contributing to strong them with their continuing discoveries. growth. And yet other chemistry professors explore enantioselective processes with no Among respiratory drugs, especially for thought for present commercialization. asthma, Erb and Zhou cite the 72% sales growth of montelukast by Merck, WhiteThere is no letup in the search for new house, N.J. Also, some companies have enantioselective methods, because each introduced new steroids, at higher prices, commercial project is unique. There is no to replace older ones. sovereign method. No matter how effective one separation, syntheIn the gastrointestinal area, Erb sis, or conversion has been in the and Zhou say that infliximab from Worldwide sales of single-enantiomer drugs head past, in the next project, economCentocor, Malvern, Pa., was origipast $123 billion ics, yield, or enantiomeric excess nally introduced to treat an SINGLE(ee) maybe lacking. inflammatory bowel disorder called ENANTIOMER DRUGS TOTAL MARKET Crohn's disease, but it now has At the beginning of develop2000 1999 $ BILLIONS 2000 1999 approval for rheumatoid arthritis. ment, however, there seems to be $26.9 Cardiovascular $46.6 $24.8 $42.7 And tamsulosin for benign proa definite place for chiral liquid 23.9 Antibiotics/ antifungals 31.7 23.9 29.3 state hyperplasia is now marketed chromatographic separation of the 14.6 Hormones 22.0 13.8 20.0 in the U.S. by Boehringer Ingelenantiomers of an active drug comCancer 10.4 9.4 15.6 13.7 heim Pharmaceuticals, Ridgefield, pound: Both enantiomers are usu9.0 Central nervous system 53.9 8.6 47.7 Conn., and Abbott Laboratories, ally needed for initial studies. ChiNorth Chicago. ral chromatography often must be 9.1 Hematology 15.4 8.6 16.5 6.5 Antiviral 19.1 6.2 17.7 developed as an analytical method, Latanaprost, marketed by Phar6.1 Respiratory 40.5 5.1 36.5 so extending the methodology to macia, Peapack, N.J., is a single3.5 3.0 Gastrointestinal 47.2 43.9 preparative work is straightforenantiomer ophthalmic drug for ward. And if a drug candidate fails glaucoma that has become the lead2.0 3.0 7.3 Vaccines 6.5 early on, not much will be lost, having drug for this disease in the U.S., 2.0 7.4 Ophthalmic 7.1 1.8 ing done preliminary work with Europe, and Japan. 18.4 1.3 Dermatological 17.9 1.2 chiral chromatography Among cardiovascular drugs, 1.3 Analgesic 23.0 1.0 21.5 5.6 Other 41.9 5.5 39.0 The increasing method of choice Erb and Zhou say the so-called for such separation is simulated statins for inhibition of cholesterol TOTAL $360.0 $390.0 $115.0 $123.3 moving bed (SMB) chromatograbiosynthesis are chiral drugs that phy (C&EN, June 19,2000, page are replacing other achiral cholesSOURCE: Technology Catalysts International 17). Besides drug firms that have terol-lowering drugs. Examples are
Drug sales
The drug industry will continue to spur strong growth in chiral compounds because of efforts to improve drug efficacy and to cut development costs. 46
C & E N / MAY 1 h, 2001
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ASYMMETRIC CRYSTALLIZATION Strecker reaction makes amino acids
o
Ç6H5
N^^COoNHo
/
(CH 3 ) 3 C—CH + H 2 N ^ C O N H 2
(CH3)3
(/?)-Phenylglycinamide
Ç6H5
/
HoS0A
HN^^CONHo
X C^H CAHc
HN^^C0NH2 (CH 3 ) 3 C^
(CH3)3C
N
HN^^C0NH2 ( C H 3 ) 3 C ^ CN
Crystallizes out
| H 2 Pd
NH9
NH9 HCl
(CH3)3C
(CH3)3C^CO H (S)-tert-Leucine
installed SMB for themselves, an increasing number of fine chemicals companies offer SMB as a contract service to special order. Examples include Aerojet Fine Chemicals of Rancho Cordova, Calif;
Bayer of Leverkusen, Germany; Chiral Technologies of Exton, Pa.; Universal Pharma Technologies of North Andover, Mass.; and the CarboGen Laboratories subsidiary of Solutia in Aarau, Switzerland.
In SMB, six to 12 chiral chromatographic columns are joined in a circle. Four to five pumps keep the liquid phase circulating through the system. As the racemate travels through the columns, a zone of one enantiomer starts to lead the rest of the bolus, while a zone of the opposite enantiomer lags behind. At intervals, under computer guidance, some of the lead enantiomer and some of the trailing enantiomer are withdrawn and saved separately At the same time, a new charge of racemate is injected into the center of the traveling bolus, while some pure liquid phase is injected 180° opposite to that point. At CarboGen, MarkusJuza, director of SMB technology, says the company's system separates 4 kg of racemic drug per day when it is up and running. CarboGen has delivered 60 kg of resolved drug racemate in a total of 16 weeks, he says. The CarboGen system is divided among three separate suites for mixed solvent preparation, the SMB apparatus itself, and product recovery This design allows maximum flexibility and rninimizes chances of cross-contamination of solvents and products.
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2001
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COVER STORY In conceiving new enantioselective technology, the search goes on among the usual alternatives: use of the chiral pool, resolution of racemates, and asymmetric synthesis. Either chemical or biocatalytic methods may be used. By chiral pool, prac titioners mean all the carbohydrates, amino acids, lipids, terpenes, and alkaloids from plant and animal sources. But recently there's been a change of thinking about what constitutes the chiral pool. The new thinking recognizes that any synthetic enantiomer that becomes available through large-scale production should also be included conceptually in the chiral pool. Perhaps the beginnings of this view came from availability of huge amounts of L-aspartic acid and L-phenylalanine at what is now Great Lakes Fine Chemicals, Mount Prospect, 111., stemming from processes developed to make the syn thetic sweetener aspartame.
inhibitors and matrix metalloprotease inhibitors. In the synthesis, (^-phenylglycine amide reacts with pivalaldehyde in Enzyme tackles tough racemates water to form an imine. The imine reacts reversibly with an added mix of sodium cyanide and acetic acid to give the two diastereomers of the corresponding amino Racemic ni trile. T h e desired diastereomeric amino H20 nitrile corresponding to (R)-phenylglycine AnEH and (S)-tert-leucine crystallizes out preferentially. Because the cyanide adds reversibly across the imine double bond, the upshot after 24 hours of stirring is the crystallization of a 93% yield of the desired 43% yield diastereomer in a 99:1 ratio. >99% ee Acid-catalyzed hydrolysis of the nitrile amide yields the diamide. Because phenylglycine is a benzylamine, hydrogénation of the diamide cleaves the phenylacetic acid CH 2 0H portion of the molecule, leaving the former amino group of phenylglycine with 43% yield the new tert-leucine portion. The synthe62% ee sis ends with further acid-catalyzed hydroSO PLENTIFUL is L-aspartic acid at Great lysis oftert-leucme amide to the amino acid. Lakes that the company uses it as a sub AnEH = Aspergillus niger epoxide hydrolase ee = enantiomeric excess Another development at DSM involves strate with transaminase enzymes to fur that firm's collaboration with academic nish the amino group in production of other single-isomer amino acids. This is synthesis of amino acids [Org. Lett., 3,1121 investigators. Broxterman and senior researcher Birgit Schulze in Geleen work actually a case of throwaway chirality (2001)]. DSM produces large amounts of with chemistry professors Roland Furstoss The person who has formalized this (iO-phenylglycine to make the semisyn and Alain Archelas of the University of the expanded concept of the chiral pool is thetic penicillin ampicillin and the Mediterranean in Marseille and their Ph.D. organic chemistry professor Eric N.Jacobcephalosporin cephalexin. The investiga student Yvonne Genzel. sen of Harvard University. He presented tors include research fellows Q. B. (Rinus) his views at the San Diego national meet The object is to develop epoxide hydroBroxterman and Wilhelmus H.J. Boesten ing of the American Chemical Society in lase enzymes for kinetic resolution. The and chemist Ben de Lange at DSM and April. obvious means of getting at enantiomeric chemistsJean-Paul G. Seerden and Richard epoxides or the corresponding diols are Jacobsen has contributed to such an M. Kellogg at Syncom. expansion of the chiral pool by devising the asymmetric epoxidation of olefins or They choose a synthesis of (S)-tertcatalytic processes amenable to large-scale hydrolytic kinetic resolution of epoxides leucine ( L ^ ^ ^ - t r i m e t h y l a l a n i n e ) to asymmetric epoxidation, epoxide ring invented by Jacobsen of Harvard or the exemplify the process. teri-Leucine is a opening, epoxide resolution, and Strecker asymmetric dihydroxylation of olefins component of some H I V protease syntheses of amino acids. Rhodia invented by organic chemistry proChiRex, Boston, has licensed the fessor K. Barry Sharpless of Scripps FURANONES Jacobsen processes and is producing Research Institute. Cyanohydrins yield heterocycles 10-metric-ton quantities of singleBut these reactions involve metal isomer epichlorohydrin, 3-chlorocatalysts. A hydrolase method has 0 OH propane-l,2-diol, propylene oxide, the advantage of involving only the (S)-HNL propylene glycol, propylene car substrate, product, water, and a H,C C 6 H 5 CH + HCN *CN 5^6 bonate, styrene oxide, methyl glybiodegradable protein. Also, the cidate, and glycidyl />-tolueneBr DSM/Marseille workers want a CH, sulfonate and /77-nitrobenzenemethod that would work with H3C Zn sulfonate at the company's plant in pyridyl-substituted epoxides, which Br Dudley, England. HRC A "CN are intermediates in making βadrenergic receptor agonists and One company that has taken its antiobesity drugs. The heterocyclic own such expansion of the chiral nitrogen, however, can form com pool to further production is DSM HCI Fine Chemicals. Chemists at the plexes with metals, interfering with DSM technical center in Geleen metal-catalyzed reactions. 0H2 NH 2 and at the contract research firm Furstoss and Archelas call their Aminofuranone Tetronic acid derivative Synthon in Groningen, both in the epoxide hydrolases "new enzymes," 93% ee 96% ee Netherlands, have reported using because chemists are finding them (S)-HNL = (S)-hydroxy η it rile lyase from Hevea brasiliensis DSM's (K)-phenylglycine as a chiral increasingly now in microorgan ee • enantiomeric excess auxiliary in an asymmetric Strecker isms, whereas until recently, knowl48
C& EN / MAY 1 A,
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KINETIC RESOLUTION
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edge of them was limited to mammalian sources. Availability of such a hydrolase 0XAZ0LIDIN0NES from Aspergillus niger means that the gene Boronate route yields can be cloned and overexpressed for pro intermediates duction in commercial amounts. With 2^C0NH2 (2-pyridyl)oxirane from epoxidation of 2ΝΗ,ΟΗ I vinylpyridine, they get a 43% yield (of a possible 50%) of (5)-epoxide in greater ;o _ U H O ^CH 2 OH than 99% ee and 43% of diol in 62% ee. They can optimize enantiomeric excess of either the epoxide or diol by running the reaction short of or past the 50% mark. N= C= 0 Onefine-chemicalscompany strategy is to construct a chemical "tree," in which the firm starts with a simple material and creates "branches" by reactions extending from the original compound. At DSM, such core materials are enantiomeric cyanohydrins, which the company makes from aldehydes and hydrogen cyanide, mediated by a hydroxynitrile lyase. The HOCH company has commercialized an (5)-lyase from the rubber tree Hevea brasiliensis and an (L)-lyase from jack beans. Working with R&D head Michael Hart Project manager Peter Poechlauer of mann and chemical engineer Herbert DSM in Linz, Austria, described elabora Mayrhofer, Poechlauer esterifies (5)-mantion of cyanohydrins to heterocyclic inter delonitrile, prepared from benzaldehyde, mediates at the San Diego ACS meeting. with α-bromopropionic acid. Treatment
of that ester with zinc gives an aminofuranone in 96% ee, which hydrolyzes to a tetronic acid in 93% ee. ANOTHER CHEMIST who has spent years working out the branches of his chemical tree is organic chemistry professor Rawle I. Hollingsworth of Michigan State Uni versity East Lansing. He founded Synthon Chiragenics in MonmouthJunction, Ν J., to sell the intermediates and technologies he has developed. And in November 2000, he signed a four-year agreement with Cambrex, East Rutherford, N.J., to develop and produce single-enantiomer compounds for making drugs. Hollingsworth will continue to develop intermediates, and Cambrex will produce them on a large scale. Some years ago, Hollingsworth per fected an alkaline hydrogen peroxide oxi dation of lactose to (5)-P-hydroxybutyrolactone and of L-arabinose to the (R)-lactone. Lactose is a coproduct of cheese making, while arabinose is plenti ful in sugar beet processing waste. He has parlayed these lactone starting materials into several dozen three-, four-, and fivecarbon asymmetric building blocks.
RESINS & CHIRAL BUILDING BLOCKS NH2 (
