161760-09-4Relevant articles and documents
Di- tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir
Dietz, Jule-Philipp,Ferenc, Dorota,Jamison, Timothy F.,Gupton, B. Frank,Opatz, Till
, p. 789 - 798 (2021/03/01)
Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).
Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment
Ambrosi, Andrea,Bringley, Dustin A.,Calimsiz, Selcuk,Curl, Jonah,Garber, Jeffrey A. O.,Huynh, Huy,Kwong, Bernard,Lapina, Olga,Leung, Edmund,Lin, Lennie,Martins, Andrew,McGinitie, Teague,Mohan, Sankar,Phull, Jaspal,Roberts, Ben,Rosario, Mary,Sarma, Keshab,Shen, Jinyu,Shi, Bing,Standley, Eric A.,Wang, Li,Wang, Xueqing,Yu, Guojun
supporting information, p. 1247 - 1262 (2021/05/29)
Phosphonamidate 1 is a key fragment in the assembly of rovafovir etalafenamide, a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection. An early manufacturing route, relying on simulated moving bed (SMB) chromatography for the separation of phosphorus diastereomers, was executed on scale to produce multiple batches of 1. However, developing alternative synthetic conditions became desirable in consideration of the high production cost, long lead time, and high process mass intensity (PMI) associated with SMB. Several strategies to improve these factors are described herein, including epimerization and recycling of the undesired (R)-phosphorus diastereomer, design of stereoselective approaches to establish the desired (S)-configuration at phosphorus, and identification of conditions or derivatives to allow for selective crystallization. Ultimately, a second-generation route to 1 was developed and demonstrated on scale. The new route achieves the separation of phosphorus diastereomers by means of selective crystallization, does not require SMB, and offers lower PMI, cost, and lead time.
An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines
Arduengo, Anthony J.,Cardoso, Flavio S. P.,Derstine, Brenden P.,Dietz, Jule-Phillip,Gupton, B. Frank,Herrera, Brenden T.,McQuade, D. Tyler,Opatz, Till,Paymode, Dinesh J.,Peck, Cheryl L.,Snead, David R.,Stringham, Rodger W.,Tomlin, John W.,Yue, Andrew C.
supporting information, p. 1420 - 1427 (2020/10/12)
Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a convergent one-step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by avoiding an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access.
Synthesis and antiviral activities of hexadecyloxypropyl prodrugs of acyclic nucleoside phosphonates containing guanine or hypoxanthine and a (S)-HPMP or PEE acyclic moiety
Tichy, Tomas,Dracinsky, Martin,Krecmerova, Marcela,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan
, p. 307 - 314,8 (2020/07/31)
Hexadecyloxypropyl esters of acyclic nucleoside phosphonates containing guanine (G) or hypoxanthine (Hx) and a (S)-[3-hydroxy-2-(phosphonomethoxy) propyl] [(S)-HPMP] or 2-(2-phosphonoethoxy)ethyl (PEE) acyclic moiety have been prepared. The activity of the prodrugs was evaluated in vitro against different virus families. Whereas ester derivatives of PEEHx and (S)-HPMPHx were antivirally inactive, monoesters of PEEG, and mono- and diesters of (S)-HPMPG showed pronounced antiviral activity against vaccinia virus and/or herpesviruses. Monoesters of (S)-HPMPG emerged as the most potent and selective derivatives against these DNA viruses. None of the compounds were inhibitory against RNA viruses and retroviruses. Crown Copyright
Synthesis of phosphonomethoxyethyl or 1,3-bis(phosphonomethoxy)propan-2-yl lipophilic esters of acyclic nucleoside phosphonates
Vrbková, Silvie,Dra?ínsky, Martin,Holy, Antonín
, p. 11391 - 11398 (2008/03/13)
A new alternative synthetic pathway towards mono and diesters of acyclic nucleoside phosphonates (PMEA, PMEC and PMEG) or [1,3-bis(phosphonomethoxy)propan-2-yl]adenine bearing one or two hexadecyloxypropyl ester groups (CH2)3O-n-Csu
NEW POSSIBILITIES OF SYNTHESIZING 5'-O-PHOSPHONOMETHYL DERIVATIVES OF NUCLEOSIDES AND THEIR ANALOGS
Yas'ko, M. V.,Novikov, N. A.,Tarusova, N. B.
, p. 36 - 39 (2007/10/02)
The corresponding 5'-O-phosphonomethyl derivatives have been obtained by alkylating the sodium derivatives of pyridine and purine nucleosides and analogs of them with p-toluenesulfonyloxymethylphosphonic acid and its monoethyl ester.Alkylation with this reagent enables the synthesis of phosphonomethyl derivatives fairly selectively at the 5'-O-aliphatic hydroxyl.The possibility of a one-step synthesis of 5'-O-phosphonomethyl nucleoside derivatives has been shown using p-toluenesulfonyloxymethylphosphonic acid.Keywords: nucleosides, nucleotides, analogs.
