Efficient Synthesis of Gemcitabine 5′-O-Triphosphate Using Gemcitabine 5′-O-Phosphoramidate as an Intermediate

Renata Kaczmarek; Ewa Radzikowska; Janina Baraniak

doi:10.1055/s-0034-1378353

Synlett, Inhaltsverzeichnis

Synlett 2014; 25(13): 1851-1854
DOI: 10.1055/s-0034-1378353

letter

Efficient Synthesis of Gemcitabine 5′-O-Triphosphate Using Gemcitabine 5′-O-Phosphoramidate as an Intermediate

Renata Kaczmarek

^aDepartment of Bioorganic Chemistry, Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland Fax: +48(42)6815483 eMail: baraniak@cbmm.lodz.pl

,

Ewa Radzikowska

^aDepartment of Bioorganic Chemistry, Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland Fax: +48(42)6815483 eMail: baraniak@cbmm.lodz.pl

,

Janina Baraniak*

^aDepartment of Bioorganic Chemistry, Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland Fax: +48(42)6815483 eMail: baraniak@cbmm.lodz.pl

^bInstitute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University, Armii Krajowej 13/15, 42-201 Częstochowa, Poland

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Abstract

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Abstract

A new efficient approach for the synthesis of gemcitabine triphosphate has been developed. The method is based on the ring-opening reaction of 2-cyanoethoxy-2-oxo-1,3,2-oxathiaphospholane with protected gemcitabine in the presence of DBU. Subsequent treatment of gemcitabine monophosphate with DCC in the presence of ammonia provides gemcitabine 5′-O-phosphoramidate. Finally, this compound, on reaction with pyrophosphate, furnishes gemcitabine 5′-triphosphate in 50% yield.

Key words

oxathiaphosphorylation - gemcitabine 5′-O-phosphate - gemcitabine 5′-O-phosphoramidate - gemcitabine 5′-O-triphosphate

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Referenzen

References and Notes
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21 Experimental Procedure for the Synthesis of Compound 16 Compound 1 was dissolved in a mixture of 2 M NH₄OH and formamide, and to this solution DCC dissolved in t-BuOH was added. The reaction mixture was heated at 80 °C for 10 h and then allowed to stand overnight at r.t. The mixture was evaporated in vacuo, and the product was isolated by ion-exchange chromatography in 78% yield. ³¹P NMR (202.45 MHz, D₂O): δ = 9.41 ppm. ¹H NMR (500 MHz, D₂O): δ = 7.80–7.76 (d, 1 H), 6.19–6.13 (t, 1 H), 6.08–6.02 (d, 1 H), 4.41–4.37 (m, 1 H), 4.14–4.10 (m, 1 H), 4.08–4.01 (m, 1 H), 4.00–3.96 (m, 1 H) ppm. ESI-MS [M – 1]: m/z = 341.
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23a Experimental Procedure for the Synthesis of Compound 15 Compound 16 was dissolved in anhydrous DMF, and bis-(tri-n-butyl)ammonium pyrophosphate (17) in DMF was added. After heating the homogeneous solution in a stoppered flask at 65 °C for 13 h the mixture was evaporated, and the product was isolated using HPLC in 50% yield. ³¹P NMR (202.45 MHz, D₂O): δ = –10.43 (d), –11.04 (d), –22.59 (t) ppm. ¹H NMR (500 MHz, D₂O): δ = 7.83–7.80 (d, 1 H), 6.14–6.09 (t, 1 H), 6.08–6.05 (d, 1 H), 4.46–4.38 (m, 1 H), 4.29–4.23 (m, 1 H), 4.18–4.13 (m, 1 H), 4.08–4.04 (m, 1 H) ppm. MALDI-MS [M – 1]: m/z = 501.7.

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