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.
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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
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Gallou, F. (2015). Development of a Manufacturing Process for the Formation of a Nucleoside Drug Candidate. In: ÄŒasar, Z. (eds) Synthesis of Heterocycles in Contemporary Medicinal Chemistry. Topics in Heterocyclic Chemistry, vol 44. Springer, Cham. https://doi.org/10.1007/7081_2015_152
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DOI: https://doi.org/10.1007/7081_2015_152
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