Commercial-Scale Synthesis of Protected 2′-Deoxycytidine and Cytidine Nucleosides

Divakar, K. J.; Sawant, Chitra M.; Mulla, Y. A.; Zemse, Deepak V.; Sitabkhan, Sakina M.; Ross, Bruce S.; Sanghvi, Yogesh S.

doi:10.1081/ncn-120022956

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…The drawbacks, however, include numerous laborious reaction steps or the formation of various by-products, due to a lack of stereo- and regioselectivity, which necessitates the implementation of protection and deprotection steps [ 5 , 6 ]. Hence, often only low product yields are obtained, even after process optimization [ 7 , 8 , 9 , 10 ]. In contrast, chemo-enzymatic synthesis routes offer a suitable alternative, as biocatalysts are active in water-based reaction media and show high selectivity.…”

Section: Introductionmentioning

confidence: 99%

Production of Modified Nucleosides in a Continuous Enzyme Membrane Reactor

Thiele

Yehia

Krausch

et al. 2023

IJMS

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Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocatalysts until their full inactivation, they offer a valuable alternative to batch enzymatic reactions with freely dissolved enzymes. In EMRs, the enzymes are retained in the reactor by a suitable membrane. Immobilization on carrier materials, and the associated losses in enzyme activity, can thus be avoided. Therefore, we validated the applicability of EMRs for the synthesis of natural and dihalogenated nucleosides, using one-pot transglycosylation reactions. Over a period of 55 days, 2′-deoxyadenosine was produced continuously, with a product yield >90%. The dihalogenated nucleoside analogues 2,6-dichloropurine-2′-deoxyribonucleoside and 6-chloro-2-fluoro-2′-deoxyribonucleoside were also produced, with high conversion, but for shorter operation times, of 14 and 5.5 days, respectively. The EMR performed with specific productivities comparable to batch reactions. However, in the EMR, 220, 40, and 9 times more product per enzymatic unit was produced, for 2′-deoxyadenosine, 2,6-dichloropurine-2′-deoxyribonucleoside, and 6-chloro-2-fluoro-2′-deoxyribonucleoside, respectively. The application of the EMR using freely dissolved enzymes, facilitates a continuous process with integrated biocatalyst separation, which reduces the overall cost of the biocatalyst and enhances the downstream processing of nucleoside production.

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