An improved synthesis of adefovir and related analogues

Jones, David J.; O’Leary, Eileen M.; O’Sullivan, Timothy P.

doi:10.3762/bjoc.15.77

Cited by 11 publications

(5 citation statements)

References 56 publications

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“…[26] The alkyl iodide used in the preparation of 19 was recently exploited as an advanced intermediate in the synthesis of several antiviral analogues and demonstrates that more complex, drug-like, alkylating agents are compatible with our methodology. [27] In summary, a robust methodology for the synthesis of various S-alkyl organophosphorus compounds has been presented. We have demonstrated the application of disulfide 2 as a shelf-stable sulfur transfer reagent for the preparation of S-(2-cyanoethyl)phosphorothioates, phosphonothioates and phosphinothioates in high yields.…”

Section: Methodsmentioning

confidence: 99%

A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

2020

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A robust methodology for the synthesis of phosphorothioates, phosphinothioates and phosphonothioates, including those bearing low molecular weight S-alkyl side-chains, is presented. Application of the "caesium effect" in conjunction with the disulfide 3,3'-dithiobis(propionitrile), which acts as a shelf-stable sulfur source, avoids recourse to malodorous alkanethiols and toxic PÀ Cl precursors. A diverse range of sulfur-containing organophosphorus targets, including phosphorus-based heterocycles, may be prepared in consistently high yields. This chemistry also provides ready access to the corresponding DBU salts which are potential substrates for Pd-catalysed coupling reactions. Scheme 3. Investigation of substrate scope of telescoped process. a) R 3 I (1.0 mmol), r.t., 3 h; b) R 3 Br (1.00 mmol), reflux, 3 h.

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Section: Methodsmentioning

confidence: 99%

A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

2020

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“…Under the traditional synthetic technology in the conventional reactor, the molar ratio of raw materials (phosphite ester and HCHO) ranged from 1:1.0 to 1:1.3, reaction temperature ranged from 100 C to 120 C, reaction pressure ranged from 3 kPa to 5 kPa, and reaction time ranged from 1h to 5 h. [12][13][14] Because the reaction was extremely exothermic, the targeted HPs exhibited significantly increased byproducts with high acid value (AN), in turn, led to low purity and low yield. [15][16][17][18][19] Stowell et al 20 studied the preparation of HPs with paraformaldehyde and dialkyl phosphite/trialkyl phosphite as raw materials in the presence of triethylamine catalyst. The results indicated that the products showed high AN in the range of 2.6 mg KOH g -1 and 3.5 mg KOH g -1 .…”

Section: Hydroxymethylmentioning

confidence: 99%

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

WANG,

LIU,

WANG

et al. 2024

Rev.Roum.Chim.

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Hydroxymethyl phosphonates (HPs) are important organic chemical raw materials and intermediates. HPs are generally synthesized by phosphite esters and formaldehyde using the conventional organic synthesis device. It shows the disadvantages of strong heat-release and more by-products for the reaction, and high acid number (AN), low yield and low purity for the product. We have designed a microfluidic reactor to synthesize HPs that can overcome above mentioned disadvantages. During the microfluidic reaction process, a series of reaction conditions can be controlled precisely. According to adopt the optimal reaction conditions, five HPs were obtained with low AN (＜0.15 mg KOH/g), high yield (＞94%) and high purity (＞99%). The designed microfluidic reactor can reduce labor cost, save equipment area, and cut down the amount of wastewater. The synthesis process can also realize continuous production and scale-up production with no amplification effect.

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“…Other methods utilize reaction of dialkyl tosyloxymethylphosphonate with an appropriate 9-(2-hydroxyethyl)purine derivative ( Figure 4A ) or reaction of an analogous purine 2-iodoethyl derivative with diethyl hydroxymethylphosphonate ( Figure 4B on the example of adefovir). The advantage of the latter one is commercial availability of diethyl hydroxymethylphosphonate ( Jones et al, 2019 ).…”

Section: Acyclic Nucleoside Phosphonates (Anps)mentioning

confidence: 99%

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

et al. 2022

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Compounds with a phosphonate group, i.e., –P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called “open-ring” derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44–80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

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An improved synthesis of adefovir and related analogues

Cited by 11 publications

References 56 publications

A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

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