20187-82-0Relevant articles and documents
Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment
Siler, David A.,Calimsiz, Selcuk,Doxsee, Ian J.,Kwong, Bernard,Ng, Jeffrey D.,Sarma, Keshab,Shen, Jinyu,Curl, Jonah W.,Davy, Jason A.,Garber, Jeffrey A. O.,Ha, Sura,Lapina, Olga,Lee, Jisung,Lin, Lennie,Park, Sangsun,Rosario, Mary,St-Jean, Olivier,Yu, Guojun
, p. 1263 - 1274 (2021/05/29)
Fluorinated nucleoside 1 is a key starting material in the synthesis of rovafovir etalafenamide (2), a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV. While an initial manufacturing route enabled the production of 1 to support clinical development, alternative approaches were explored to further enhance manufacturing effectiveness, improve processing time, reduce cost, and minimize the environmental impact. Toward this end, two new routes were developed to a key synthetic intermediate, which was converted to 1 using a new protecting group strategy. The new chemistry led to improvements in the manufacturing process while reducing the overall process mass intensity (PMI).
Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús
, p. 4406 - 4416 (2018/09/14)
The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.
Syntheses of 2′-deoxy-2′-fluoro-β-d-arabinofuranosyl purine nucleosides via selective glycosylation reactions of potassium salts of purine derivatives with the glycosyl bromide
Sivets, Grigorii G.
supporting information, p. 268 - 271 (2016/01/12)
Syntheses of 9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-guanine (1) and -adenine (2) were accomplished from readily available 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-d-arabinofuranose (3). A new and efficient approach for the synthesis of 1-α-bromide was developed using the mild bromination of α-1-O-benzoate (3). Selective coupling reactions of the bromosugar with purine potassium salts followed by derivatization/and or deprotection of the intermediate blocked 2′-fluoro β-arabinonucleosides resulted in formation of the target compounds with high overall yields.
