SCIENCE & TECHNOLOGY
CHIRAL CRAVINGS Customers want to produce single-enantiomer compounds fast and cost-effectively S T E P H E N C. S T I N S O N , C & E N N O R T H E A S T NEWS B U R E A U
A
T THE CHIRASOURCE 2 0 0 1
symposium in Philadelphia last month, conferees returned to the perennial topic of how best to produce single-enan tiomer compounds. Thinking is often heavily influenced by chemical suppliers' presentations, which stem from their point of view as providers either of single tech nologies or of complete "toolboxes" of many such methods. Keynote speaker James Mack, who is board chairman and chief executive officer of Cambrex Corp., East Rutherford, N.J., challenged that point of view by stating, "It's all about the customer." And Thomas Waldman, who is director of research and development at Solutia Pharmaceutical Services, Basel, Switzerland, echoed Mack's point by asking, "So what does the customer really want?" As Waldman put it: "Does the customer want a tools-based approach? No. The cus tomer simply wants pure active pharma ceutical ingredients for testing and launch." Waldman continued, "Customers want pure material fast for preclinical testing; limited process research and development until assured of a winner; a reliable, scala ble process on demand; and no major route changes after {early} clinical trials." Commenting on today's climate in chiral and other fine chemicals generally Mack called it a "lumpy business." Because of mergers and acquisitions, big pharmaceu tical companies have "pulled back on out sourcing, but the outsourcing business will come back." There is less capital available to emerging pharmaceutical companies. "There has been a cut in U.S. interest rates," Mack said, "but the banks are tightening credit." And as to the regulatory environ ment: "It seems to be unpredictable, nonuniform, and, to me, unclear. Some companies thought they had straight tracks. Then came requests for more information. Some had to abandon products." In his answer to what the pharmaceuti cal customer wants, Mack cited speed, quality of science, and cost-effective prod ucts and services. Focusing on "quality of science," Mack explained: "We have to have the same quality of science as the pharmaceutical firms. They trust only HTTP://PUBS.ACS.ORG/CEN
Chemical catalysts are selective and give broad control of structures, Waldman said, and chemists have invented hundreds of asymmetric transition-metal ligands and all-organic catalysts. But process devel opment times are long, ligands and met als are costly, and reaction conditions are challenging. Waldman stressed that fine chemical suppliers must avoid long process devel opment times. As a result of mergers and acquisitions, "aggressive growth targets and full pipelines force 'early kill' strate gies in drug development."This is the op posite attitude of nursing a questionable compound along because "it's our baby" Waldman explained, "The customer ex pects to fail. So they can't wait for process development." Lack of a good process can hamper a company's economics all the years of a drug's life. This is because after a point in clinical development, the process is locked in. If the process were changed and prop erties such as the drug's impurity profile changed also, all of the preclinical and tox-
themselves, talk only among themselves, and hire from among themselves. We have to be as good as they are." Solutia's Waldman surveyed the range of entries to chiral compounds that are ac cessible to chemists. The advantages to us ing the "chiral pool" of natural products as raw materials are wide availability low cost, and "biological fit." By biological fit, Wald man means that natural products often have biological activity, so derivatives and com binatorial scaffolds based on natural prod ucts have high probabilities of biological activity as well. The downside is that struc tural control is limited, and the compounds require isolation and purification. Fermentations or enzyme-catalyzed transformations are selec tive, efficient, and cost-ef MOLECULAR RECOGNITION fective, Waldman said, but Racemates separated without chromatography the processes have long de velopment times and high π-π interaction capital costs. Resolutions of racemates are easy to de velop in a short time, and H3C there are several process types available. But yields are low if the "wrong" iso H 3 N* mer cannot be racemized, H-bonding and the processes are hard to commercialize.
ASYMMETRIC Avecia's catalytic route to cyanohydrin derivatives CCHi CHO
HCI
KCN
COoH 99% ee
Si(CH3)3 CHO
(CH3)3SiCN
(CAH9)oAIH
CH 2 NH 2 99% ee
Catalyst:
Λ"
ο
η VSHD+
ee = enantiomeric excess
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SCIENCE & TECHNOLOGY icological testing would be invalidated by the Food & Drug Administration. In this framing of narrow windows for process development, Waldman sees a role for a specialty of Solutia's CarboGen subsidiary in Aarau, Switzerland: simulated moving bed (SMB) liquid chromatography (LC). Chiral SMB uses an endless circle of columns packed with a chiral stationary phase, often derivatized cellulose. As the slug of racemate travels through the columns, one enantiomer starts to pull ahead, while the other lags behind. A computer guides the withdrawal of enantiomers from rear and leading edges, as well as injection of more solvent and racemate in the middle. The virtue of the technique is that it uses less solvent than linear LC and is scalable at CarboGen to 60-some k per campaign. Thus, the drug company can get a supply of active ingredient for continued testing while buying time to devise an economical process. But Jean Bléhaut, chief operating officer of NovaSep Inc., Boothwyn, Pa., objected in Philadelphia that conventional SMB can suffer from overkill. The usual
DIAZO COMPOUNDS Large-scale cyclopropanation
N = N-CHC0 2 C 2 H 5
Catalyst
H
3CΛ
Cl
' I
CH
"ΤCH3
H3C H 2 C^ C H 2 CH3
fixed withdrawal and injection points mean that an integral number of columns must be in each phase of the cycle. That process can be inefficient, as more column volume than is needed sometimes must be used.
Workers at NovaSep S.A.S., Pompey, France, have devised a timed shifting of the locations of withdrawal and injection points to allow for devoting only the col umn length needed to each phase of the process. They have trade-named their process Varicol, and Bléhaut referred to the result as an "SMB chronogram." "Large-scale Varicol systems typically have five columns," he said, 'Svhereas most largescale SMB systems have six." With the chiral stationary phase priced at $7,500 perk, the difference matters. John A. J. Blacker, technical manager of process technology at Avecia Life Science Molecules, Huddersfield, England, described the company's developing technology in asymmetric cyanohydrin derivatives, organozincs, molecular recognition, and sulfur ylides. Avecia gives its catalytic asymmetric cyanohydrin technology the acronym CACHy, reminiscent of its catalytic asymmetric transfer hydrogénation, CATHy The company has been developing CACHy in collaboration with organic chemistry professors Michael North at King's College, London, and Yuri Ν. Be-
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EPOXIDES Aggarwal chemistry commercialized C6H5CHN
/ N NaOCH i
5
6
H NaOTs
Ts = C H 3 C 6 H 4 S 0 2 -
lokon' at Nesmeyanov Institute of Organoelement Compounds, Moscow Their cat alyst is vanadyl or titanium ion chelated by the Schiff base of 3,5-di-ter£-butyl-2-hydroxybenzaldehyde with either enantiomer of ir^w-l,2-diaminocyclohexane. The key is to generate the cyanohydrin with a protected hydroxyl group to pre vent the reverse reaction and degradation of the enantiomeric excess (ee). In one such transformation, 0-chlorobenzaldehyde reacts with potassium cyanide and acetic anhydride to give, after acid hydrolysis, (R )-2-chloromandelic acid in 99% ee. Similarly nicotinaldehyde reacts with trimethylsilyl cyanide to give the silylated cyanohydrin, which is reducible by diisobutylaluminum hydride to (R)-l-(3pyridyl)-2-aminoethanol in 99% ee. FOR ASYMMETRIC reactions of organozincs, Avecia has gone beyond the usual di methyl or diethyl compounds. For exam ple, the company forms the Grignard reagent of chlorobenzene and treats that with zinc chloride to get diphenylzinc. The key is to add toluene to the reaction mix ture while evaporating the ether to pre cipitate magnesium and zinc salts, which would catalyze a nonstereoselective addi tion of the organozinc. Blacker gave the example of addition of diphenylzinc to mtrifluoromethylbenzaldehyde catalyzed by Ν,Ν-dimethylnorepinephrine to give 3-trifluoromethylbenzhydrol in 86% ee. The disadvantage of higher organozinc reagents is that only one substituent re acts, wasting the other one. Blacker indi cated the possibility of using mixed reagents such as methyl-3-methoxy-5-trifluoromethyiphenylzinc, or methyl-4-carbethoxy-1-butenylzinc, which would react to add only the aryl or vinyl portion while wasting only a methyl group. Although Blacker mentioned Avecia's development of a nonchromatographic molecular recognition approach to the sepHTTP://PUBS.ACS.ORG/CEN
for the particular racemate. Although the method uses packed columns, the prin ciple is bind-and-release rather than chromatogra C H CHO phy The crown ether binds such compounds as the enantiomers of l-(l-naphthyl)ethylamine hydrochlo ride both by hydrogen 'C H bonding of the ammonium protons to the crown het60% yield 93% ee eroatoms and by π-jt dona tion of electrons from naph thalene to pyridine. The racemate solution aration of racemates, the agreement li passes through the first column to give an censing the technology from IBC Ad 80/20 enriched product stream. Next, the vanced Technologies, American Fork, aqueous medium is adjusted to flush a Utah, was too new for him to describe it in 20/80 stream enriched in the opposite detail. The process uses columns of an im enantiomer. Each stream passes through mobilized chiral receptor like the crown two more such columns, which enrich each ether pyridine-18-crown-6, made from to 98.5% ee.Theflushingsof intermediate 2,6-bis^ydroxymethyl)pyridine, ethylene enrichment from all the columns are re turned to earlier phases of the process for glycol, and ©-propylene glycol. The liquid medium is water rather than further enrichment. The sulfur ylide chemistry that Avecia organic solvents, with pH and ionic strength adjusted to give the best results is developing was invented by synthetic 6
5
6
5
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Ç*H 5
HN^C0NH 2 D
^f^^^CH2
NH2 H 2 ,Pd/C t
0
"CH-,
