Advances in Custom Synthesis

February 2, 2010
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-02-02-2010, Volume 34, Issue 2

As contract manufacturers and drug companies meet at Informex, the stage is set for the latest in pharmaceutical chemical development.

Seeking ways to improve or achieve the synthesis of an active pharmaceutical ingredient (API) or intermediate used in the synthesis of an API is an ongoing task for contract manufacturers, pharmaceutical companies, research centers, and universities. Some recent advances in asymmetric synthesis, natural product synthesis, and green chemistry are improving select synthethic routes.

Patricia Van Arnum

Asymmetric synthesis

Synthesizing enantiomerically pure compounds is an important area of process research and development. Researchers at Ohio State University in Columbus, Ohio, reported on the use of parallel kinetic synthesis, whereby a single catalyst transformed a racemic mixture of aziridines to a pair of regioisomeric products with good yield and high enantioselectivity (1). The researchers used a dimeric yttrium salen catalyst to accelerate the ring opening of aliphatic aziridines by trimethylsilylazide, thereby inducing nucleophilic attack at the primary position of one enantiomer and the secondary position of the other (1).

(PHOTO: MIRIAM MASLO/SPL, SCIENCE PHOTO LIBRARY, GETTY IMAGES)

In another development, researchers at Rutgers University in New Brunswick, New Jersey, advanced an approach for enantioselective amine acylation. The researchers reported on the use of a small-molecule catalyst to acylate amines enantioselectively. Specifically, the researchers described that acyl pyridinium salts derived from 4-(dimethylamino)pyridine and benzoic anhydride are made chiral from the interaction with a chiral thiourea anion receptor (2).

Natural products

Natural products provide potential drug candidates, but the synthetic route to a natural product can be difficult to achieve. A recent breakthrough was reported by researchers at the Scripps Research Institute in La Jolla, California, who successfully synthesized palua'amine, a complex alkaloid that has shown potential as a possible anticancer, antibacterial, and antifungal agent. The compound is derived from a sponge off Palau, an island nation in the Pacific Ocean. The compound was discovered in 1993, but the complexity of the molecule has made its synthesis very challenging, according to a Jan. 7, 2010, Scripps Research Institute press release.

The compound has eight contiguous stereogenic centers, several reactive nitrogen-containing moieties, and a highly strained core that forms a junction between two five- membered rings (3). Scripps Research chemist Phil Baran, who led the team that made the breakthrough, has been working on the synthesis since he arrived as a faculty member at Scripps Research more than six years ago, according to the release.

The key breakthrough was a cyclization strategy to make the strained core (3). The synthesis of palau'amine was achieved via highly chemoselective transformations, cascade reactions, and a transannular cyclization to secure the trans-5,5 ring junction (4). One of the more significant later advances was applying silver-mediated oxidation, which stabilized an intermediate to permit the five final steps to a macro-paula'amine, according to the release.

Nanoburrs: a novel nanoparticle in drug delivery

Another group of researchers at Scripps Research Institute reported on a strategy for aryl carbon–hydrogen olefination, an approach that may be useful for synthesizing natural products and other drugs. The palladium-catalyzed Mizoroki–Heck reaction, which couples aryl halides with olefins, is widely used to forge carbon–carbon bonds (5). But this approach has certain disadvantages, namely installing the halide of interest is not always easy, according to a Dec. 3, 2009 Scripps Research Institute release. An alternative method, palladium-catalyzed carbon–hydrogenation olefination, has been limited to specific cases that generally include electron-rich heterocyles and/or stoichiometric palladium (5). The researchers instead used a carboxylate-directed palladium (II)-catalyzed carbon–hydrogen olefination reaction using phenylacetic acid and 3-phenylpropionic acid substrates with oxygen at atmospheric pressure as the oxidant and amino-acid derivatives as the ligands. This approach was used to produce commercial drug scaffolds and to synthesize 2-tetralone and naphtholic acid natural product cores (5).

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

References

1. B. Wu, J.R. Parquette, T.V. RajanBabu, Science 362 (5960), 1662 (2009).

2. C. Kanta De, E.G. Klauber, and D. Seidel, J. Amer. Chem. Soc. 131 (47), 17060–17061 (2009).

3. C. Drahl, Chem. Engin. News 88 (2), 5 (2010).

4. I.B. Seiple et al. Agnew. Chem. Intel. Ed. Engl., DOI://10:1002/anie.200907112 (2010).

5. J. Quan Yu et al., Science 327 (5963), 315–319 (2010).

6. I. Andrews et al., Org. Process Res. Dev. 14 (1), 19–29 (2010).

7. P. Van Arnum, "Deploying Green Chemistry in API Synthesis," Pharm. Technol. Sourcing and Management, July 8, 2009, PharmTech.com/ptsm.

8. EPA, Green Chemistry Challenge Agency Awards Program: Summary of 2009 Award Entries and Recipients (Washington, DC, 2009).

9. B.H. Lipshutz et al., Org. Lett. 10 (7), 1325–1328 (2008).

10. B.H. Lipshutz et al., Org. Lett. 10 (7), 1329–1332 (2008).

11. B.H. Lipshutz et al., Org. Lett. 10 (7), 1333–1336 (2008).

12. L.R. MacGillivray, J. Org. Chem. 73 (9), 3311–3317 (2008).

13. L.R. MacGillivray et al., Acc. Chem. Res. 41 (2), 280–291 (2008).