Green chemistry
Members of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable, which includes major pharmaceutical
companies and select fine-chemical producers, recently published a review article that highlighted green-chemistry articles
of interest to the pharmaceutical industry (6). Some highlights include several approaches relating to so-called green oxidation,
which primarily focused on improved oxidation methods to avoid the use of stoichiometric metal oxidants or by using oxidants
that lessened the amount of waste (6). Some strategies include an aerobic oxidation of amines to carbonyl compounds based
on catalytic copper with stoichiometric ascorbic acid as the oxidative mediator and oxygen as the terminal oxidant (6). In
another development, a catalytic aerobic oxidation of allylic alcohols to the corresponding aldehyde or ketone was developed
using a water-soluble platinum tetrasulfophthalocyanine catalyst (6).
Asymmetric hydrogenations is an important reaction in pharmaceutical chemical development. Some recent approaches include
the use of iron catalysts in asymmetric hydrogenation and transfer hydrogenation of ketones to provide a more cost-effective
and greener approach than palladium and ruthenium catalysts (6).
Biocatalysis also is an important tool. Some recent developments include a process for resolving amines using a transaminase
with an amino-acid oxidase and a catalytic amount of pyruvate as the amine receptor (6).
Continuous processing is an emerging field in API development. The review article highlights the application of continuous
hydrogenation of a pharmaceutical intermediate using a continuous-stirred tank reactor for reducing a dinitro compound and
the use of continuous processing in a biocatalytic route.
Several entries in the 2009 Presidential Green Chemistry Challenge Awards, an annual recognition by the US Environmental Protection
Agency, provide approaches in green chemistry with applications to the pharmaceutical industry (7, 8). Bruce H. Lipshutz,
professor in the chemistry and biochemistry department of the University of California at Santa Barbara, developed an approach
to increase reaction efficiency and enhance catalytic activity, thereby reducing the level of organic solvents used in certain
chemical reactions (7, 8). Lipshutz and his team found that a mono-PEGylated, alpha-tocopherylated sebacid acid derivative
(PTS) allows several common organic reactions catalyzed by transition metals, particularly palladium and ruthenium, to use
water as the only solvent, to be run at room temperature, and produce product in high isolated yield. PTS may be used under
mild aqueous conditions for olefin-metathesis reactions, palladium-catalyzed Suzuki, Heck, and Sonogashira cross-couplings
(9–11). By permitting the catalysis under aqueous conditions, PTS eliminates the use of organic solvents in these reactions
(7, 8).
PTS functions as a surfactant. It is a nanomicelle-foaming amphiphile that features vitamin E or tocopheral as the inner lipophilic
solvent with a 10-carbon linker and PEG-600 hydrophilic portion. Under aqueous conditions, the micelles formed in the PTS
function as nanoreactors that allow for high concentration of reactants and catalysts within these micelles to increase reaction
rates. The increased activity allows the reaction to be run at ambient temperatures. PTS is covered by patents owned by the
National Research Council in Canada, a research and development organization of the Canadian government, and is under exclusive
license to the bioscience company Zymes (Hasbrouck Heights, NJ) (7, 8).
Leonard R. MacGillivray, a professor in the chemistry department at the University of Iowa, developed a method using small-molecule
templates to assemble olefins (which undergo intermolecular [2+2] photodimerization) in discrete assemblies for solid-state
reactions. The solid-state arrangements of the olefins are controlled by the template rather than by the long-range crystal
packing. MacGillivray used this method for the solid-state synthesis of ladderanes, building blocks for natural products,
and reported regiospecificity, no byproducts, and a 100% yield. Such an approach allows molecules to react in geometries and
orientations that are typically inaccessible in solution (7, 8, 12, 13).
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com
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