Advances in Asymmetric Synthesis - Pharmaceutical Technology

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Advances in Asymmetric Synthesis
Researchers forward approaches for catalytic hydroformylation, asymmetric hydrogenation, and biocatalysis to achieve enantioselectivity.


Pharmaceutical Technology


Enzymes can be an economic alternative to chemocatalysts in asymmetric reactions. Biocatalysis may be used, for example, to make precursors for RNA interference drugs. As an example, David Rozell, vice-president of enzyme products and services of the Pharma Services Group at Codexis (Redwood City, CA) points to 2'-O-methoxyethyl guanosine derivatives that are produced by means of a chemo-enzymatic sequence that relies on a reaction catalyzed by adenosine deaminase as a key step.

Biocatalysts may also be used in reductive amination. Amino-acid dehydrogenases may be used to convert 2-ketoacids to the corresponding -amino acid, says Rozzell. L-tert-leucine and L-cyclopentylglycine are two examples of unnatural amino acids that are manufactured by Codexis.

"While enzymes for producing L-amino acids are well-known, nature does not provide amino-acid dehydrogenases for the reductive amination of ketoacids for the synthesis of D-amino acids," says Rozzell. Codexis recently commercialized D-selective amino-acid dehydrogenases developed by BioCatalytics (18). Codexis acquired Biocatalytics (Pasadena, CA) earlier this year.

Other new enzyme platforms developed by BioCatalytics include transaminases for producing chiral amines and enone and enoate reductases for the selective reduction of C=C bonds.

Chiral separations

In addition to asymmetric synthesis and synthesis from chiral pools, resolution by chromatography is a widely accepted method for obtaining single enantiomers.

"Chromatography is one possible way to reach pure enantiomers," explains Geoffrey B.Cox, vice-president of Chiral Technologies (West Chester, PA). "In working under tight time constraints, the development groups in the pharmaceutical industry use chiral chromatography as the fastest method to obtain single enantiomer materials." Modern preparative chromatography systems allow for easy separation of racemic mixtures and the production of gram to multikilo quantities in a few days.

Separations at larger scale are carried out by simulated moving bed (SMB), which is essentially a binary chromatographic separator and has the advantage of being a continuous process. This technique is therefore particularly suited to the separation of enantiomers at pilot and production scale.

In one recent case study, "we needed a process capable of delivering 90 metric tons per year of a specific pharmaceutical intermediate," explains Cox. After economic analysis of the possible processes, the decision was made to use SMB technology for this project. Based on the throughput that was achieved in this particular case, the cost to separate the single enantiomer from the racemic mixture was less than $100/kg. Even more compelling are cases in which the undesired enantiomer can be reracemized and recycled through the SMB. There are seven pharmaceuticals that use this process.

Supercritical fluid chromatography used with chiral stationary phases also is a way to resolve enantiomers.With SFC, most of the liquid solvent is replaced by pressurized carbon dioxide, and only a small percentage of an organic solvent is required to solubilize the compound and serve as a cosolvent with the carbon dioxide (19). Regis Technologies (Morton Grove, IL) recently added SFC to its separations services.

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,
.

References

1. M. Beller and K. Kumar, "Hydroformylation: Applications in the Synthesis of Pharmaceuticals and Fine Chemicals," in Transition Metals for Organic Synthesis, M. Beller, C. Bolm, Eds. (Wiley-VCH, Weinheim, Germany 2004), Vol. 1, pp. 29–55.

2. B. Breit, "Synthetic Aspects of Stereoselective Hydroformylation," Acc. Chem. Res. 36 (4), 264–275 (2003).

3. I. Ojima and K. Hirai, "Asymmetric Hydrosilylation and Hydrocarbonylation," in Asymmetric Synthesis, J.D. Morrison, Ed. (Academic Press, New York, 1985), Vol. 5, pp. 126–145.


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