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Development of a Manufacturing Process for the Formation of a Nucleoside Drug Candidate

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Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 44)

Abstract

The original synthesis of our oral prodrug of isatoribine, a nucleoside analogue potentially useful for the treatment of patients with chronic hepatitis C and other viral infections, suffered from various limitations. Herein we would like to report a practical and robust process identified for the synthesis of an isatoribine prodrug therefore in the course of our process R&D activities. Our efforts relied on the practical manufacture of the base in a straightforward sequence in a streamlined glycosylation process, followed by an effective and regioselective enzymatic hydrolysis, both with a much improved environmental impact. The catalytic activity of the immobilized lipase was demonstrated to be very robust as the enzyme displayed an excellent behavior as catalyst with high levels of activity, selectivity, and excellent operational stability. This process was further developed in a semicontinuous mode and demonstrated to proceed in an even more efficient manner from a throughput standpoint.

Keywords

Glycosylation Heterocycle Immobilized lipase 

Abbreviations

2-MeTHF

2-Methyltetrahydrofuran

Ac

Acetyl

API

Active pharmaceutical ingredient

BSA

Bis-silylacetamide

DMAP

Dimethyl aminopyridine

DMF

Dimethylformamide

GMP

Good manufacturing practice

h

Hour(s)

HMDS

Hexamethyldisalazane

HSE

Health safety, environment

kin

Kinetic

Me

Methyl

MTBE

Methyl-tert-butyl ether

PAT

Process analytical technology

rt

Room temperature

SM

Starting material

Tf

Triflate

Therm

Thermodynamic

THF

Tetrahydrofuran

TMS

Trimethylsilyl

References

  1. 1.
    Xiang AX, Webber SE, Kerr BM, Rueden EJ, Lennox JR, Haley GJ, Wang T, Ng JS, Herbert MR, Clark DL, Banh VN, Li W, Fletcher SP, Steffy KR, Bartkowski DM, Kirkovsky LI, Bauman LA, Averett DR (2007) Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine. Nucleosides Nucleotides Nucleic Acids 26:635–640CrossRefGoogle Scholar
  2. 2.
    Gallou F, Seeger-Weibel M, Chassagne P (2013) Development of a robust and sustainable process for nucleoside formation. Org Process Res Dev 17:390–396CrossRefGoogle Scholar
  3. 3.
    Fletcher S, Steffy K, Averett D (2006) Masked oral prodrugs of toll-like receptor 7 agonists: a new approach for the treatment of infectious disease. Curr Opin Investig Drugs 7(8):702–708Google Scholar
  4. 4.
    Anderson NG (2012) Practical process research and development – a guide for organic chemists, 2nd edn. Academic, AmsterdamGoogle Scholar
  5. 5.
    Anastas PT, Warner JC (1998) Green chemistry: theory and practice. Oxford University Press, New YorkGoogle Scholar
  6. 6.
    Anastas PT, Zimmerman JB (2003) Through the 12 principles of green engineering. Environ Sci Technol 37(5):94A–101ACrossRefGoogle Scholar
  7. 7.
    Roschangar F, Sheldon RA, Senanayake CH (2015) Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept. Green Chem 17:752–768CrossRefGoogle Scholar
  8. 8.
    Vorbrueggen H (1995) Adventures in silicon-organic chemistry. Acc Chem Res 28(12):509–520CrossRefGoogle Scholar
  9. 9.
    Jutz C (1976) Iminium salts in organic chemistry. Wiley, New YorkGoogle Scholar
  10. 10.
    Hanessian S, Banoub J (1977) Chemistry of the glycosidic linkage. Carbohydr Res 59:C13–C16CrossRefGoogle Scholar
  11. 11.
    English JP, Clark H, Clapp JW, Seeger D, Ebel RH (1946) J Am Chem Soc 68:453CrossRefGoogle Scholar
  12. 12.
    D’Amico JJ, Bollinger FG, Freeman JJ (1988) Synthesis of 2-oxo and 2-thioxo-3(2H)-benzothiazoleethanimic acid anhydride with acetic acid and related products. J Heterocycl Chem 25(5):1503–1509CrossRefGoogle Scholar
  13. 13.
    Li N-S, Piccirilli JA (2006) Efficient synthesis of 2′-C-β-methylguanosine. J Org Chem 71(10):4018–4020CrossRefGoogle Scholar
  14. 14.
    Jimenez-Gonzalez C, Ponder CS, Broxterman QB, Manley JB (2011) Using the right green yardstick: why process mass intensity is used in the pharmaceutical industry to drive more sustainable processes. Org Process Res Dev 15(4):912CrossRefGoogle Scholar
  15. 15.
    Palomo JM, Filice M, Fernandez-Lafuente R, Terreni M, Guisana JM (2007) Regioselective hydrolysis of different peracetylated β-monosaccharides by immobilized lipases from different sources. Key role of the immobilization. Adv Synth Catal 349(11):1969–1976CrossRefGoogle Scholar
  16. 16.
    Orrenius C, Norin T, Hult K, Carrea G (1995) The Candida antarctica lipase B catalysed kinetic resolution of seudenol in non-aqueous media of controlled water activity. Tetrahedron Asymmetry 6(12):3023–3030CrossRefGoogle Scholar
  17. 17.
    Dicosimo R, Payne MS, Croud VB, Gavagan JE, Wagner LW, Hann EC (2007) US 20070042924Google Scholar
  18. 18.
    Kinoshita M, Ohno A (1996) Factors influencing enantioselectivity of lipase-catalyzed hydrolysis. Tetrahedron 52(15):5397–5406CrossRefGoogle Scholar
  19. 19.
    Kitamoto Y, Kuruma Y, Suzuki K, Hattori T (2015) Effect of solvent polarity on enantioselectivity in Candida antarctica lipase B catalyzed kinetic resolution of primary and secondary alcohols. J Org Chem 80(1):521–527CrossRefGoogle Scholar
  20. 20.
    Burke PA, Griffin RG, Klibanov AM (1993) Solid-state nuclear magnetic resonance investigation of solvent dependence of tyrosyl ring motion in an enzyme. Biotechnol Bioeng 42(1):87–94CrossRefGoogle Scholar
  21. 21.
    Margolin AL, Tai DF, Klibanov AM (1987) Incorporation of D-amino acids into peptides via enzymic condensation in organic solvents. J Am Chem Soc 109(25):7885–7887CrossRefGoogle Scholar
  22. 22.
    Sakurai T, Margolin AL, Russell AJ, Klibanov AM (1988) Control of enzyme enantioselectivity by the reaction medium. J Am Chem Soc 110(21):7236–7237CrossRefGoogle Scholar
  23. 23.
    Dordick JS (1992) Designing enzymes for use in organic solvents. Biotechnol Prog 8(4):259–267CrossRefGoogle Scholar
  24. 24.
    Takahashi K, Tamaura Y, Kodera Y, Mihama T, Saito Y, Inada Y (1987) Magnetic lipase active in organic solvents. Biochem Biophys Res Commun 142(2):291–296CrossRefGoogle Scholar
  25. 25.
    Talukder MM, Rahman B, Ko LM, Song OP, Pu S, Wu J, Chuan W, Jae C, Chow Y (2008) Improved method for efficient production of biodiesel from palm oil. Energy Fuels 22(1):141–144CrossRefGoogle Scholar
  26. 26.
    Secundo F, Carrea G (2002) Lipase activity and conformation in neat organic solvents. J Mol Catal B: Enzym 19:93–102CrossRefGoogle Scholar
  27. 27.
    Gallou F, Beney P US 20110091943Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Chemical and Analytical Development, Novartis Pharma AGBaselSwitzerland

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