Advancing Chiral Chemistry in API Synthesis - Pharmaceutical Technology

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Advancing Chiral Chemistry in API Synthesis
Functionalized supramolecular catalysts and an enantioselective route to unnatural amino acids are some recent developments.


Pharmaceutical Technology
Volume 33, Issue 11, pp. 44-50

Biocatalysis at work

An example of a successful process substitution using biocatalysis was recently reported for producing an intermediate used in the synthesis of aliskiren, a renin inhibitor used to treat hypertension. A key step in the synthesis of aliskiren is an enzymatic resolution catalyzed by pig-liver esterase (PLE). PLE is a versatile biocatalyst because it has a broad substrate spectrum and excellent enantio- and regio-selectivity. Commercially available PLE is animal derived, which can result in variability. To address this problem, DSM (Heerleen, The Netherlands) and its collaboration partner, the Graz University of Technology in Austria, identified different isoforms of PLE. Using capabilities in enzyme development and production, a highly efficient and patented microbial expression system and fermentation process was developed for different isoforms of PLE that runs at a 25,000-L scale at DSM. This system delivers nonanimal-derived PLE isoforms (PharmaPLEs, DSM) at a large scale for pharmaceutical applications (13).

In another development, researchers at Merck & Co. (Whitehouse Station, NJ) reported on the pilot-scale asymmetric synthesis of 4,4-dimethoxytetrahydro-2H-pyran-3-ol with a ketone reductase and in situ cofactor recycling using glucose dehydrogenase in high yield and enantiomeric excess (11, 12).

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. D. Uraguchi, Y. Ueki, and T. Ooi, Science 326 (5949), 120–123 (2009).

2. S.J. Zuend et al., Nature 461 (7266), 968–970 (2009).

3. Y. Lu, T.C. Johnstone, and B.A. Arndtsen, J. Am. Chem. Soc. 131 (32), 11284–11285 (2009).

4. M. Penner et al., J. Am. Chem. Soc. 131 (40), 14216–14217 (2009).

5. P. Van Arnum, Pharm. Technol. 32 (9), 60–64 (2008).

6. E. Balskus and E. Jacobsen, Science 317 (5845), 1736–1740 (2007.)

7. J. Kim, J.A. Ashenhurst, and M. Movassaghi, Science 324 (5950), 238–241 (2009).

8. J. E. Wilson, A.D. Caserez, and D.W.C. MacMillan, J. Am. Chem. Soc. 131 (32), 113332–11334 (2009).

9. P. Van Arnum, Sourcing and Management, July 8, 2009, http://PharmTech.com/ptsm.

10. T.V. RajanBabu et al., J. Am. Chem. Soc., 130 (25), 7845–7847 (2008).

11. P. Van Arnum, Sourcing and Management, Sept. 1, 2009, http://PharmTech.com/ptsm.

12. I. Andrews et al., Org. Process Res. Dev. 13 (3), 397–408 (2009).

13. P. Van Arnum, Pharm. Technol. 33 (9) API Synthesis and Formulation suppl. s34–s38 (2009).


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