science/technology
HIGH TIMES FOR FINE CHEMICALS Dynamic companies expand their 'trees' of products, develop processes with less waste, court academic expertise Stephen C. Stinson C&EN Northeast News Bureau
Boston in May and last month's Chemical Specialities Europe 97 (ChemSpec Eu rope) conference and exposition in he fine chemicals industry these days Manchester, England. looks a lot like the biotechnology in Often, the technological advances by dustry did 20 years ago. Small firms fine chemicals producers have led to pro are starting up, often organized around a cesses that create less waste to treat or single technological capability. Larger firms compounds that extend branches of com are looking to buy some of these smaller, panies' "chemical trees." A chemical tree specialized companies, to forge strategic is a group of compounds related to one alliances with them, or to establish their another by their origin in a common start own entrepreneurial divisions. And every ing material such one is chasing chemistry professors who as ketene, hydro have newly patented technology. gen cyanide, malThis upbeat tone was strongly reflect onate esters, or eped in two recent meetings of the fine oxybutene. These chemicals community—the Chiral USA growing technolo 97 symposium and exposition held in gy portfolios of
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fine chemicals producers are increasingly important to their customers, not only be cause they want to buy them as starting materials but also because customers often want to have similar compounds made to special order. Several chemistry professors have de veloped technologies that are attracting the attention of fine chemicals produc ers. Among them are Michael P. Doyle of Trinity University, San Antonio, Texas; Xumu Zhang of Pennsylvania State Uni versity, University Park; Yian Shi of Colo rado State University, Fort Collins; and Varinder K. Aggarwal of the University of Sheffield, England. Doyle's asymmetric dirhodium carboxamidate catalysts have been patented for Trinity by Research Corp. Technolo gies, Tucson, Ariz., and licensed to Regis Technologies, Morton Grove, 111. Chem ist Marina Protopopova of Regis de scribed asymmetric syntheses with the Doyle catalysts to the Chiral USA 97 sym posium in Boston.
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JULY 14, 1997 C&EN 37
seience/technology Doyle catalysts mediate fins that are huge commerreactions of diazo com cial successes. The enantioEnantioselective Doyle catalysts... pounds with olefins to form meric epoxides that result cyclopropanes or with car are in demand as intermediC0 2 CH 3 bon-hydrogen bonds to ates in drug production. form new carbon-carbon The Sharpless technology bonds by insertion between is licensed to Sipsy of Avthe carbon and hydrogen rillé, France, and Jacobsen's atoms. The reactive inter to ChiRex of Wellesley, mediate is a carbene from Mass. decomposition of the diazo Shi's catalyst is attractive ... mediate cyclopropanations... compound. The catalyst because it works without a orients the carbene and transition metal and the H substrate for an asymmetric starting material for the catCatalyst reaction. alyst itself is an inexpensive 'CH 2 ' * ,CH 2 II sugar. He ties up four hyThe catalysts consist of Ο droxy! groups of the pyratwo rhodium ions linked nose form of D-fructose as together and chelated by Cyclopropane analog of γ-aminobutyricacid a bis(acetonide) and oxidizfour molecules of an enan es the remaining one to a tiomeric ligand. The ligand keto group. The resulting can be a methyl ester of 5.and carbon-hydrogen insertions chiral ketone functions in hydroxy-2-pyrrolidinecaran asymmetric catalytic cyboxylic acid, 2-hydroxy-4cle, becoming oxidized by oxazolidinecarboxyiic acid, OChU Cata| st potassium monopersulfate or l2CH2OCH3 v to a dioxirane, which ephydroxy-4-imidazolidinecaroxidizes the olefin subboxylic acid. θ' XHN? strate. Shi suggested that a Protopopova cites in Pyrrolizidine base catalyst that induces chiralitramolecular reaction of Nty in the opposite sense allyldiazoacetamide as an Two or three of the substituents on might result from use of the inexpensive, example of cyclopropanation. The prod uct is a single-isomer cyclopropane ana phosphorus are electron-donating alkyl naturally occurring ketohexose, L-sorbose. Aggarwal, a reader in organic chemislog of the neurotransmitter γ-aminobutyr- groups rather than less electron-donating ic acid, which finds use in studies of aryl groups, Zhang pointed out, a differ try at Sheffield, also makes enantiomeric drugs for anxiety, depression, and epilep ence that heightens catalytic activity in hy epoxides in a catalytic cycle, but from alsy. One of her examples of C-H bond in drogénations. Following the tradition of as- dehydes. For example, as he explained at sertion is intramolecular reaction of 1-di- signing nicknames to chiral phosphine cat- Chiral USA 97, he converts benzaldehyde azoacetyl-2-methoxymethylpyrrolidine. alyst ligands, Zhang has dubbed one of his and phenyldiazomethane to one isomer of frans-stilbene oxide. This reaction opens routes to total syn compounds PennPhos. theses of pyrrolizidine bases. This technology is attractive because Zhang demonstrates his catalysts by Enantioselective catalysis is also the showing enantiomeric excess (ee) of 97 it leads from a carbonyl compound diheart of Zhang's technology. The Perm to 99% in hydrogénations of oc-acetamino- rectly to an enantiomeric epoxide. In State assistant professor also described acrylic acids to iV-acetylated amino acids. comparison, the asymmetric olefin ephis approach at Chiral USA 97. Informed And the ee is 97% in base-catalyzed alky- oxidations of Shi, Sharpless, and Jacobsources suggest that fine chemicals pro lation of an allylic acetate by dimethyl sen start with an asymmetric olefin, ducer Catalytica of Mountain View, Calif, malonate. Future work at Perm State in- which is often made by a Wittig reaction may be about to license the Perm State cludes hydrogénation of Schiff bases to on a carbonyl compound. enantiomeric amines. This will be a spepatent. In Aggarwal's catalytic cycle, phenylZhang makes enantiomeric ligands bear cial challenge because of the lability of diazomethane reacts with a copper(II) ing two substituted phosphino groups. Schiff bases and their existence as syn complex to give a copper phenylmethyl carbene. The copper carbene reacts with These groups chelate such transition met and anti geometrical isomers. als as rhodium or palladium to yield cat Shi, an assistant professor at Colo- an enantiomeric dialkylsulfide to form a alysts for asymmetric hydrogénation or rado State, discussed his fructose-based dialkylphenylmethylsulfonium ylide. Agalkylation. asymmetric epoxidation catalyst at Chiral garwal makes the enantiomeric disulfide Chemists have made thousands of USA 97. The university has patented his from commercially available camphor-πchiral phosphines over the past 20 years in invention, but Shi says that only a few sulfonyl chloride. In the final step of the efforts to invent new asymmetric catalyst companies are now approaching to dis- cycle, the chiral sulfur ylide transfers the phenylmethyl group asymmetrically to ligands. What makes Zhang's approach dif- cuss licensing. ferent is that he has attached the phosphoOrganic chemistry professors K. Barry benzaldehyde to yield the single-isomer rus atoms to or made them a part of rigid Sharpless of Scripps Research Institute, frans-stilbene oxide. rings. He said that therigidityallows better La Jolla, Calif., and Eric N. Jacobsen of If Aggarwal can perfect two addition transfer of chirality from the catalyst to the Harvard University have each invented al applications of his technology, interest reacting molecules. catalytic asymmetric epoxidations of ole- from fine chemicals producers could be-
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38 JULY 14, 1997 C&EN
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science/technology come intense. One application is produc tion of terminal epoxides; the other is an asymmetric Darzens reaction. Currently, to make a terminal epoxide such as ei ther enantiomer of styrene oxide, the re action incorporates benzaldehyde and diazomethane via the sulfur ylide catalytic cycle. Diazomethane is too toxic and tricky to handle in industry, but Aggarwal suggests that an organometallic like bis(chloromethyl)zinc [Zn(CH2Cl)2] might substitute. In one example of the conventional Darzens reaction, base-catalyzed reaction
of benzaldehyde with ethyl oc-chloroacetate gives racemic ethyl phenylglycidate. Although there is much interest in an asymmetric version of this reaction, no one has devised one. Aggarwal hopes to meet this goal by fashioning an asymmet ric sulfur ylide-mediated reaction of alde hydes with A^Akliethyldiazoacetamide.
Production with less waste In addition to combing through chemistry professors' patents, fine chem icals producers are innovating on their own. One trend is toward cleaner pro-
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cesses that avoid costs of treating waste. For example, researchers at Thomas Swan & Co., Crookhall, U.K., see prom ise in such reactions as catalytic hydrogénation in supercritical carbon dioxide, which avoids using an organic solvent. Scientists at Solvay Interox, Widnes, England, are exploring oxidations by hydrogen peroxide catalyzed by metal silicates. These reactions produce water as the only coproduct. Further along that line, workers at Rhône-Poulenc, Vénissieux, France, are investigating the specific role of heterogeneous catalysis in the oxidation of phenol by hydrogen peroxide in a clean route to vanillin. Other companies are also exploring cleaner reaction routes. Ube Industries, Ube, Japan, promotes its dimethyl carbonate as a substitute for phosgene for production of polycarbonate resins. Cross-linked crystals of the enzyme penicillin acylase may reduce reaction volumes during production of antibiotics, according to Altus Biologies, Cambridge, Mass. And PTC Technology, Cherry Hill, N.J., advocates phase-transfer catalysis as a means of reducing reaction volumes, avoiding toxic solvents like methylene chloride, and eliminating costly reagents. A process can be cleaner if it runs in a smaller plant or at a faster rate, organic research chemist Stephen K. Ross of Thomas Swan told a symposium at
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phenol to catechol and water. Reaction Then they treat the crystals with a crossof the catechol with methanol yields linking agent such as glutaraldehyde. guaiacol plus water. Condensation with Cross-linking the protein protects the en formaldehyde leads to vanillyl alcohol, zyme from denaturation during reactions and air oxidation of that benzyl alcohol in organic solvents, at extremes of pH, and at temperatures as high as 60 °C. results in vanillin plus water. Use of penicillin acylase in immobi Ube Industries makes the dimethyl carbonate that it hopes will displace lized form was pioneered by Boehringer phosgene in fine chemicals production Mannheim of Mannheim, Germany. The by reaction of carbon monoxide with enzyme catalyzes hydrolysis of the phemethyl nitrite catalyzed by palladium(II) nylacetyl side chain from penicillin G to acetate. The nitric oxide coproduct is re make 6-aminopenicillanic acid (6-APA). cycled with methanol and oxygen to Lalonde said that the CLEC form is 100 times as active as the immobilized form. make more methyl nitrite. By changing the conditions, antibiot The enzyme preparation that Altus Bi ologies offers for antibiotic production is ics producers can use the CLEC enzyme an extension of its cross-linked enzyme to attach new side chains to 6-APA to crystal (CLEC) technology. As staff scien produce the so-called semisynthetic pen tist Jim Lalonde explained at Chiral USA icillins. Incubation of 6-APA with D97, Altus workers crystallize purified phenylglycine produces ampicillin and penicillin acylase from Escherichia colt. incubation with D-//-hydroxyphenylgly-
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science/technology Expositions competing for exhibitors, attendees Symposia and expositions like Chemical Specialities Europe 97 keep fine chemi cals suppliers and customers up to date on the latest offerings of compounds, tech nologies, and services. But all through 1997, people in the industry are watching a final play-off of the battle of the shows: How many expos can attendees and ex hibitors afford to attend, and which events will make the cut? In 1996, the Synthetic Organic Chemi cal Manufacturers Association (SOCMA) held both its traditional, highly valued Informex custom chemicals exposition as well as a new TriLife Expo on outsourc ing in the drug, pesticide, and biotechnol ogy industries. And the organizers of the hugely successful Conferences on Phar maceutical Ingredients (CPhls) in Europe and Asia launched their first Pharmaceu tical Ingredients—U.S. (PhlUS). Mean
cine produces amoxycillin. Similarly, re action of 7-aminodeacetoxycephalosporanic acid (7-ADCA) yields the semisyn thetic cephalosporins cefalexin and cefadroxil. Lalonde said that CLECs allow reduc tion of reaction volumes for deacylation and acylation steps, thus reducing waste water. In addition, workers do not have to isolate and purify 6-APA or 7-ADCA but can acylate them to semisynthetic an tibiotics in the same reaction mixture. Further work at Altus includes use of or ganic solvents to avoid competing hy drolysis of the β-lactam ring. Also along the line of waste reduc tion, Marc Halpern, president of PTC Technology, gave examples of uses of phase-transfer catalysis at ChemSpec Eu rope. A phase-transfer catalyst is usually a quaternary ammonium salt with one or more long-chain alkyl or benzyl substituents. Examples are tetrabutylammonium bromide and methyltridecylammonium chloride. Reaction mixtures have two immisci ble phases such as water and toluene. An organic substrate is dissolved in the or ganic phase, while the aqueous phase has an inorganic reagent. The hydropho bic chains of the quaternary ammonium salt bind to the organic substrate in the organic solvent. The cationic portion of the catalyst facilitates transport of the catalyst-substrate complex into the aque ous phase. After reaction of the substrate with the inorganic reagent, the catalyst carries the product molecule back to the organic phase. This approach avoids
while, a subset of symposia devoted to chiral chemistry continued to prosper in Europe and the U.S. Exhibitors and attendees were sparse at the 1996 Trilife Expo, however, perhaps because that show followed PhlUS by only four weeks. SOCMA has decided not to mount a TriLife Expo in 1997, but is seeking an alliance with a partner organization to put on a stronger TriLife affair in 1998. A similar situation occurred when the organizers of PhlUS repositioned their April 1997 show to occur just 11 weeks after SOCMA's Informex. PhlUS was sparsely attended in the new time slot, but the organizers say they are commit ted to keep coming back until they es tablish PhlUS in the U.S.. Fine chemicals conferences and ex positions set for the next 12 months in clude the following:
overreaction with the inorganic reagent and build-up of side products. One case Halpern cited is reaction of a benzyl chloride with sodium cyanide to
• Sept 16-18. CPhI, London. For the ex position, contact T&G Food Ingredient Services, 4220 Commercial Way, Glenview, ΠΙ 60025; phone (847) 635-9960, fox (847) 635-6801. For the symposium, con tact Manufacturing Chemist, 30 Calderwood St, London SE18 6QH, UJC; phone 44181316 3390,fox44181316 3017 • Oct 16-17. Chiral Europe '97, Lon don. Contact Spring Innovations, 185A Moss La., Bramhall, Stockport, Cheshire SK7 1BA, U.K.; phone 44 l 6 l 440 0082, fax 44 l 6 l 440 9127. • Nov. 11-13. ChiraTech 97, Philadel phia. Contact Catalyst Group, P.O. Box 637, Spring House, Pa. 19477; phone (215) 628-4447, fax (215) 628-2267. • Jan. 27-29, 1998. Informex, New Or leans. Contact SOCMA, 1100 New York Ave., N.W., Washington, D.C 20005; phone (202) 4144100,fax(202) 289-8584. • May 11-13,1998. PhlUS, Philadelphia. Contact T&G Food Ingredient Services.
form a substituted phenylacetonitrile. In particular, process chemists at ParkeDavis, Holland, Mich., have treated 40 kg of 2,4,6-triïsopropylbenzyl chloride with
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JULY 14, 1997 C&EN 4 7
Cyano Chemistry Your key to success Nitriles Aminoacetonitriles α-Hydroxy Acids Cyanohydrins Hydantoins Synthetic Amino Acids
Allyl Cyanide Diphenylacetonitrile Grycinonitrile Sulfate Dimethylaminoacetonitrile D,L-Mandelic Acid D,L-Pantolactone Mandelonitrile Methyl Propyl Ketone Cyanohydrin Hydroxybutylhydantoin Benzylidenehydantoin a-Aminoisobutyric Acid Cycloleucine Glycine
science
Vanillin process has only water coproduct
Here is just a sampling of what Hampshire's expertise in HCN chemistry can do for you. For more information contact John D. Freilich, Ph.D., Hampshire Chemical Corporation, USA Telephone 617-861-9700 Fax 617-863-8043 or Stephen Arnold, Hampshire Chemical Ltd., UK Telephone 44181579 5443 Fax 44181579 3494
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sodium cyanide in a reaction mixture of toluene and water, using tetrabutylammonium bromide as phase-transfer catalyst [Org- Proa Res. Dev., 1, 137 (1997)]. Water is a better, safer solvent for treatment of waste cyanide than the dimethyl sulfoxide used in the discovery part of their research. The process also reduces the amount of cyanide from 1.7 equivalents to 1.05. The Parke-Davis workers can also control the rate of the exothermic reaction by changing the rate of agitation of the two-phase mixture. The reaction is essentially quantitative, side reactions are minimized, no color develops in the nitrile product, and the toluene solution can be used for the next step in the process without isolation. Another of Halpem's examples is a dehydrochlorination developed by DuPont chemists to convert 3,4-dichloro-2-butene to chloroprene. The process uses only 1.008 moles of sodium hydroxide per mole of dichloro compound and yields 992% product. The catalyst is benzylbis(2hydroxypropyOcocoammonium chloride.
Broadening chemical trees Lonza of Basel, Switzerland, and Wacker Chemie of Munich, Germany, are among the fine chemicals makers
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^v ( piperazine-2carboxylic acid. That building block forms a part of the human immunodefi ciency virus protease inhibitor, indinavir. It's also part of an agent called D-CPP-ene that is used to block nerve cell death dur ing ischemic stroke. As Brieden ex plained, Lonza has combined chemical and biocatalytic methods to reach a vari ety of pyrazine intermediates. In one route, the company buys 2-cyanopyrazine, converts that to the amide, and hydrogenates the amide to racemic piperazine-2-carboxamide. Lonza uses a Klebsiella amidase to hydrolyze only the (5>amide to the corresponding acid. From there, the company synthesizes the N-4-protected te^butylamide needed for indinavir production. Alternatively, Lonza can make a tetrahydropyrazine from ethylenediamine, glyoxal, and sodium cyanide, convert that to a protected derivative, and sub-
Davos Chemical Corporation 464 Hudson Terr. • Englewood Cliffs, NJ 07632 • (201) 569-2200 • FAX (201) 569-2201 CIRCLE 52 ON READER SERVICE CARD
Your Carbodiimide Resource California Office P.O. Box 85132 San Diego, CA 92186 Phone: 800-7-TANABE Fax: 619-571-3476
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DCC (Dicyclohexylcarbodiimide) and EDC HCL (Water soluble carbodiimide).
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science
Very aromatic OH 3 - Bromophenol
3 - Fluorophenol
3 - Fluoroiodobenzene
1 - Bromo 3,5 - difluorobenzene
1 - Bromo 3,4,5 - trifluorobenzene
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3 -ί Fluoto -i 4 - hydroxyacçtophertone
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Expertise in Aromatic Specialities Substituted bromo- and fluoroaromatics, multifluorinated aromatic compounds and many more building blocks for your synthesis projects.
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CHEMICAL S P.O. Box 1053, Morristown, NJ 07962 1-800-322-2766 · FAX 1-973-455-6191 Manufactured by Riedel-de Haën AG, Germany
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ject the derivative to an asymmetric hydrogénation to reach the protected (5>2piperazinecarboxyiic acid. Wacker's acetoacetic esters come from pyrolysis of acetic acid to diketene and reaction of that with an alcohol, Pommerening explained. To make β-alkylacetoacetates, he prefers base-catalyzed condensation of an acetoacetic ester with an aldehyde, with continuous lowpressure hydrogénation of the resulting olefinic ester to the product. For example, the company treats methyl acetoacetate with hexanal to form the β-hexylidene ester, which is hydrogenated to methyl β-hexyiacetoacetate. Pommeren ing explained that alternative alkylation with an alkyl halide can lead too easily to dialkylated or Oalkylated products, and that the coproduct halide salts are a prob lem to treat in wastewater. Hydrolysis and decarboxylation of βalkylacetoacetates are the method of choice to make very pure 2-ketones, Pom merening said. Alternative routes from oxidation of olefins, dehydrogenation of secondary alcohols, or ring opening of epoxides lead to contamination by iso mers, he explained. To make acylacetates other than acetoacetates, Wacker has devised a calcium enolate method. They treat methyl aceto acetate, for example, with calcium hy droxide to produce the calcium enolate, whichreactswith an acid chloride such as />-anisoyl chloride to give methyl oc-acetyl/>-anisoylacetate. Reaction of that with aqueous ammonia causes deacetylation to methyl /Kinisoylacetate. Other methods of making acylacetates suffer from isomeric by-products or the need to use hazardous or costlyreagentsor solvents like sodium, sodium hydride, liquid ammonia, or hexamethylphosphoramide. One exception to the need to use the calcium enolate method to make very pure acylacetates is production of meth yl γ,γ,γ-trifluoroacetoacetate. At both Lonza and Rohm and Haas, reaction of diketene with trifluoroacetyl chloride proceeds cleanly to trifluoroacetoacetyl chloride, which yields the methyl ester with methanol. This methyl ester is an important in termediate to introduce a trifluoromethyl group into drugs or pesticides, which often imparts enhanced biological activ ity. For example, Rohm and Haas uses the trifluoro compound captively to make its Dimension brand of the herbi cide dithiopyr, process development man ager Fereydon Abdesakan tells C&EN. And both Lonza and Rohm and Haas
In addition to large-scale production of intermediates by Wacker grows a chemical tree from acetoacetates... firms like Lonza, Wacker, and Rohm and Haas, there is also a Pyrolysis CH market forfirmsthat can make 3OH^ CH3C02H CH2 = C = 0 GH3CCH2CO2C/H3 -+ CB 2 = x > = 0 milligram to kilogram amounts Methyl acetoacetate Ketene of key compounds for use in Diketene research projects. These re...using alkylation with an aldehyde... search compounds are often developed in academic laboratories, but the innovative invesCSHUCHO tigators there generally proCH3CCH2CO2CH3 CH3CCCO2CH3 CH3CCHCO2CH3 duce only milligram or gram II CHC5H11 quantities for their own needs. Publication of methods us...hydrolysis to 2-ketones. ing these compounds arouses the interest of drug or pesticide industry researchers. The H + orOH" CH 3 CCH2C 6 H 1 3 CH3CCHCO2CH3 academic innovators are usually generous in sharing their C6H13 small quantities, but industry researchers are often frustrat...and calcium enolates to yield acylacetates ed by supply problems. A case in point is the series of enantiomeric bicyclic CH3CCHC02CH3 lactams invented by organic O-(Ca2+)05 chemistry professor Albert I. Ca(0H)2 CH3ÇCH2CO2CH3 CH 3 C = C H C 0 2 C H 3 Meyers of Colorado State University, Fort Collins. These OCHo lactams are useful auxiliaries in asymmetric syntheses of a wide variety of compound CH3O H A 3 / — C C H 2 C 0 2 C H 3 types. They can be covalently bound to a substrate to intreat the trifluoro compound with am- of herbicides under development at Bay- troduce a chiral center and removed at monia to get methyl (^ammo^y-trifluo- er, FMC, and Novartis. Rohm and Haas the end of the synthetic organic serocrotonate. also offers alkylaminotrifluorocrotonates, quence. Interestingly, Meyers has never The aminotrifluorocrotonate is an in- in case someone discovers a lead struc- patented these auxiliaries. "I'm not a patenting type," he said smiling, noting that termediate to make the new uracil class ture that uses them also.
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PHYTOCHEMICALSI Your c o m p l e t e source Tropane Alkaloids
Arecoline
• Camptothecin
I Cultivation
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LOOK TO THE LEADER IN POTASSIUM AND BORANE BASED CHEMISTRY,
When you purchase reagents from Callery Chemical Company, you buy 50 years of experience in potassium and borane-based chemistries. We provide as little or as much assistance as you need ... from reaction concept... to pilot scale-up ... to plant design ... to production of a finished product. For specialty chemicals, look to one of the leaders — Callery Chemical Company. TO R E C E I V E A
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science the National Institutes of Health funds his work on the lactams. "I don't believe academic research should be used that way." One company that has stepped in to supply the Meyers lactams is Salford Ultrafine Chemicals & Research, Manchester, England. Team leader Stephen Stokes described syntheses of 100-g amounts at the European ChemSpec. Problems arise with making production on this scale economical because of costly or hazardous reagents called for in Meyers' original papers. The first step in his synthesis, for example, is reduction of an enantiomeric amino acid to the amino alcohol with lithium aluminum hydride. For lactams with endocyclic carbon-carbon double bonds, one procedure calls for phenylselenenyl bromide, while a second method uses potassium hydride to abstract a proton before reaction with methyl benzenesulfinate. Salford Ultrafine substitutes sodium borohydride activated by iodine for the lithium aluminum hydride reduction, Stokes explained. To get away from selenium compounds or potassium hydride, the Manchester firm uses sodium hexamethylsilazide as base before the benzenesulfinate step. Salford Ultrafine also furnishes some two dozen chirally specific substrates, inhibitors, and metabolites involved in the cytochrome P450 system of oxidizing enzymes. This system of oxidases works to hydroxylate and demethylate drug molecules and to oxidize amines. Thus, there is intense interest among drug researchers to study the variants of these enzymes. For example, concern has arisen over patients taking certain antihistamines for hay fever and allergic rashes at the same time they take certain antifungal drugs. Both of these drug types are metabolized in the liver by the same P450 enzymes, called CYP3A4 and CYP2D6. The danger is that when P450 oxidizing capacity is tied up metabolizing an antifungal drug, levels of the antihistamine could rise in the blood, provoking abnormal heart rhythms. As senior chemist Jonathan Hull explained at ChemSpec Europe, Salford Ultrafine responds to researchers' needs to study these enzyme systems by producing 100-mg batches of (5>bufuralol and a hydroxylated metabolite. Originally developed as a drug for high blood pressure, racemic bufuralol is a good substrate for CYP2D6, and the (S>enantiomer is even better. So (5>bufuralol and
its metabolite are sought to study that en zyme variant. The company uses two enzymecatalyzed reactions in sequence to en hance ee of thefinalproduct. In the first reaction, a lipasefromPseudomonas sapatia mediates conversion of a chiral secondary alcohol to a single-isomer ace tate, using vinyl acetate as both solvent and acetyl donor. In the second reaction, run in aqueous buffer, the same lipase hydrolyzes the enantiomerically enriched acetate preferentially to the secondary al cohol of the same configuration. Some firms specialize in compounds that are fairly dangerous. Phoenix Chemi cals of Wirral, England, for example, is a custom producer that specializes in such explosive intermediates as diazoketones and photosensitive azides and in danger ous processes like chloromethylation and photorytic bromination, which involve the risks of toxicity and burns. At ChemSpec Europe, the company introduced chloromethyi chlorosulfate (C1CH2S02C1) and β-bromoethyl methyl ether. The chloromethyl sulfate finds use in reactions with alcohols and acids to make chloromethyl ethers and esters. The bromoethyl derivative is used to apply a β-methoxyethoxy protecting group during multistep syntheses. Some customers of the fine chemicals industry are not so much interested in buying chemicals as in getting their own compounds custom-made. For them, demonstrated skill in handling the start ing material can help the custom manu facturer land the contract. A case in point is an advanced inter mediate for Merck's antiglaucoma drug dorzolamide. The molecule features a thiophene ring fused to a cyclic sulfone, plus two asymmetric carbon atoms. As business research associate Stewart R. Korn of Zeneca LifeScience Molecules explained at ChemSpec Europe, Merck turned to the company because Zeneca LSM had developed a process to make Dβ-hydroxybutyric acid. Merck process chemists had already devised a process to make dorzolamide that starts with the methyl ester of this acid. Zeneca LSM has since sold its hydroxybutyrate business to Monsanto. The process cultures Alcaligenes eutrophus in a medium containing glucose but no source of nitrogen. Unable to grow and divide, the organism responds by making copious amounts of the energy storage compound poly-D-β-ηνdroxybutyrate. This is hydrolyzed to the acid.
In the original Merck process, the terminal methyl group of the hydroxybutyrate becomes an (5>methyl group in a cyclic ketosulfide intermediate. A chemical reduction of the ketone pro duces mostly (R)-secondary alcohol, owing to some asymmetric induction by the (5>methyl group. But this asymmet ric induction is not total, which means added expense from a purification step by diastereoisomeric crystallization and from loss of about 10% of the potential product to unwanted isomer. Korn, se nior R&D chemist A. John Blacker, busi
ness research associate David J. Moody, and senior microbiologist Robert A. Holt at Zeneca solve this problem by substi tuting a biocatalytic reduction of the ketone. Another firm that has acquired ex pertise in enantiomeric β-hydroxy acids is NSC Technologies, Mount Prospect, 111. Senior research chemist Scott A. Laneman described his work with re search fellow David J. Ager at Chiral USA 97. The two have developed an asymmet ric hydrogénation of, for example, meth-
Experience is... Methadone HCI Normal-Phase
Reversed-Phase
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Column: CHIRALCEL* 0J™ Size: 4.6 mm I.D. χ 250 mm
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.. .the Chiral Advantage At Chiral Technologies, Inc., we focus on chiral chromatography. Our technical staff develops hundreds of new separations for you each year for normal-phase and reversed-phase chiral applications. So when you purchase our market-leading CHIRALCEL®, CHIRALPAK® or CROWNPAK® HPLC columns, you will have the support of an experienced staff who can assist you in separating your compound in the most efficient manner.
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NEW... Chiral Building Blocks with 99* % chiral purity from nature Available in kg quantities: OR 0 R
science/technology Companies make trifluoroacetoacetate... ο y\ CF3COCI + H 2 C = < > = 0
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ynthon Corporation
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yl acetoacetate to either enantiomer of the β-hydroxybutyrate at 100% conver sion and 98% ee. They use a catalyst of ruthenium chelated by either enantio mer of 2,2'-bis(diphenylphosphino)1,1 '-binaphthyl (BINAP). Asymmetric reductions by rutheniumBINAP are far from new. What Laneman and Ager find is that using chlorine atoms as the final two ligands around ruthenium makes a superior catalyst and confers oxi dative stability to it. They can store dichlororuthenium-BINAP catalysts in air for four years without loss of activity. NSC Technologies' chemists have also found an improved, less expensive synthesis of BINAP. They treat the en antiomeric 2,2/-bis(trifluoromethanesulfonate) with chlorodiphenylphosphine in the presence of nickel chloride and zinc. According to Laneman, chlorodi phenylphosphine is less expensive and easier to handle than the diphenylphosphine used in a process developed by Merck.
In addition to perfecting processes to make fine chemicals intermediates of known value, companies increasingly turn to combinatorial chemistry to dis cover lead compounds with a desired ac tivity. Combinatorial chemistry makes use of variously substituted molecular compo nents in all possible reactive combinations to create libraries of compounds for screening. But as manager E. Andrew Boyd of Oxford Diversity, Abingdon, England, pointed out at Chiral USA 97, thousands of compounds have to be created and screened for each promising lead that combinatorial chemistry produces. Even major drug and pesticide makers don't have the ability to prepare combinatori al libraries at the rate of more than 2,000 compounds per day that Boyd es timates they need to be assured of a rea sonable flow of candidate compounds for development. Oxford Diversity, a subsidiary of enan tiomeric fine chemicals producer Oxford
Asymmetry, was born out of a realization by drug giant Pfizer that thatfirmneeded to outsource its combinatorial chemical effort. Pfizer reached an initial two-year agreement with Oxford Asymmetry, renewed this year, that resulted in the foundation of Oxford Diversity. One of thefirstrequirements for a useful drug screening library is that the compounds in it be "druglike," Boyd explained. This means that the compounds have to have structural units found in real drugs, and not just units like simple amino acids that are easy to string together. Some researchers in combinatorial chemistry call these "privileged structures." Boyd could not disclose actual compound types in the 50 different libraries his company has made for Pfizer to date, so in Boston he used an example in which his company played no role, the anti-inflammatory drug candidate RG 12525 of Rhône-Poulenc Rorer. This compound has three sources of diversity that can be varied for libraries: a 2-quinolinyl, a 1,4-phenylenedioxy, and a tetrazolylmethylphenyl group. The solid-state chemistry on which combinatorial techniques are based is relatively undeveloped, Boyd said. So one of his company's achievements has been the invention of 12 different linking molecules for Pfizer, which allow library molecules to be linked to an insoluble resin during synthetic sequencing. In one of these linker systems, the resin is functionalized with amino groups. The linkagefromeach library molecule is through a 4-biphenyiyl group connected to a dimethylsilyl group, a β-propionyl group, and finally to the resin amino group. The linkage is easily applied, with stands the reaction conditions of synthetic sequences, and comes off easily at the end of the synthesis using mild ultraviolet pho tolysis in trifluoroacetic acid. Thus, the scene at such industry shows as ChemSpec Europe and Chiral USA 97 is of a youthful, innovative fine chemicals in dustry with features usually associated with the biotechnology industry. There are plenty of big firms with well-known names involved, but also small start-up companies purveying specialized slates of compounds or techniques. And there are plenty of roles for academic chemists to invent less expensive, effective ways to make useful chemicals. Customers in the drug and pesticide industries are shop ping in the fine chemicals industry not only for intermediates, but also for likely firms that can make their compounds to special order. ^
The source of synthetic matter·
Inorganics Thionyl chloride Sulfuryl chloride Açid chlorides Qiloroacetyl chloride Methoxyacetyl chloride yCyclopropanecarbonyl chloride
/Specialities v
Chloromethyl pivalate Pyridine SO3 complex ,Ν,Ν-Dimethylthiocarbamoyl chloride jl-(Chlormethyl) pyridine HCI (S^-(-)-2-Acetoxypropionyl chloride C u s t o m syntheses is our main strength
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