116384-53-3Relevant articles and documents
Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
Roux, Lo?c,Priet, Stéphane,Payrot, Nadine,Weck, Clément,Fournier, Ma?lenn,Zoulim, Fabien,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
, p. 869 - 881 (2013)
9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12.
Process optimization in the synthesis of 9-[2-(diethylphosphonomethoxy)ethyl]adenine: replacement of sodium hydride with sodium tert-butoxide as the base for oxygen alkylation
Richard,Schultze, Lisa M.,Rohloff, John C.,Dudzinski, Pawel W.,Kelly, Daphne E.
, p. 53 - 55 (1999)
9-[2-(Diethylphosphonomethoxy)ethyl]adenine (diethyl-PMEA), a key intermediate in the production of the antiviral drug adefovir dipivoxil, was originally produced via a process utilizing sodium hydride (NaH) to couple hydroxyethyl adenine with diethyl p-toluenesulfonyloxymethanephosphonate. The use of NaH presented safety and consistency problems. It was found that sodium tert-butoxide (NaOBu) was a suitable replacement for NaH as the base to effect the coupling reaction. Optimization of reagent stoichiometry and introduction of a simplified filtration workup procedure led to a robust process affording diethyl-PMEA in consistent yields and purities. The modifications and process improvements were scaled-up successfully to batch sizes of >100 kg.
An improved synthesis of adefovir and related analogues
Jones, David J.,O’Leary, Eileen M.,O’Sullivan, Timothy P.
supporting information, p. 801 - 810 (2019/04/17)
An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.
Preparation method of adefovir dipivoxil crystals
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, (2017/07/21)
The invention belongs to the technical field of drug preparation and in particular relates to a preparation method of adefovir dipivoxil crystals. The preparation method comprises the following steps: synthesizing diethyl phosphite; synthesizing diethyl (p-phenylsulfonyloxy)methylphosphonate; synthesizing 9-(2-hydroxyethyl) adenine; synthesizing 4,9-[2-(diethylphosphonomethoxy)ethyl]adenine; synthesizing adefovir; synthesizing adefovir dipivoxil. Compared with the prior art, the preparation method of the adefovir dipivoxil crystals, provided by the invention, takes acetonitrile as a water-soluble organic medium, and the difficulty that DMF (Dimethyl Formamide) is difficult to remove is overcome; ethyl acetate is used for replacing isopropyl acetate in a previous process, isopropyl ether is used for replacing ethyl ether and ethanol is used for replacing acetone; the preparation method is simple to operate; the obtained product has good purity and high yield; the industrialized production is easy to realize and the production cost is reduced.