89268-01-9Relevant academic research and scientific papers
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.
Oral Delivery of Propofol with Methoxymethylphosphonic Acid as the Delivery Vehicle
Wei, Yonggang,Qiu, Guanpeng,Lei, Bailin,Qin, Linlin,Chu, Hongzhu,Lu, Yonghua,Zhu, Guozhi,Gao, Qiu,Huang, Qingping,Qian, Guofei,Liao, Pengfei,Luo, Xinfeng,Zhang, Xiaowei,Zhang, Chen,Li, Yao,Zheng, Suxin,Yu, Yan,Tang, Pingming,Ni, Jia,Yan, Pangke,Zhou, Yi,Li, Pan,Huang, Xia,Gong, Aisheng,Liu, Jianyu
supporting information, p. 8580 - 8590 (2017/11/03)
Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.
Dynamic kinetic resolution based asymmetric transfer hydrogenation of α-alkoxy-β-ketophosphonates. Diastereo- and enantioselective synthesis of monoprotected 1,2-dihydroxyphosphonates
Son, Se-Mi,Lee, Hyeon-Kyu
, p. 2666 - 2681 (2014/04/17)
Dynamic kinetic resolution driven, asymmetric transfer hydrogenation reactions of a wide range of 2-substituted α-alkoxy-β- ketophosphonates 3 were observed to proceed efficiently to give the corresponding 2-substituted α-alkoxy-β-hydroxy phosphonates 4 w
α-Functionalized phosphonylphosphinates: Synthesis and evaluation as transcarbamoylase inhibitors
Flohr, Alexander,Aemissegger, Andreas,Hilvert, Donald
, p. 2633 - 2640 (2007/10/03)
Diverse α-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are accessible from a protected, pentafluorophenylsulfonated phosphonylphosphinate via nucleophilic displacement. The utility of this route is demonstrated with several nitrogen nucleophiles. The resulting amine and amino acid phosphonylphosphinate derivatives were evaluated as inhibitors of Streptococcus faecalis ornithine transcarbamoylase (OTC). Compared with the structurally related phosphonoacetyl-L-ornithine (L-PALO), a known inhibitor of OTCs from various sources, the phosphonylphosphinates are surprisingly poor inhibitors, binding several orders of magnitude less tightly to the enzyme. These results suggest that the tetrahedral intermediate formed in the normal transcarbamoylase reaction is poorly mimicked by a tetrahedral and anionic phosphonate, either because of directly unfavorable interactions with a hydrogen-bond acceptor within the active site or because transition-state analogues are unable to induce the protein conformation changes that normally accompany reaction.
A Convenient One-pot Synthesis of Polyenic Enol Ethers
Vo-Quang, Yen,Carniato, Denis,Vo-Quang Liliane,Goffic, Francois Le
, p. 1505 - 1506 (2007/10/02)
Diethyl alkoxymethylphosphonates react with unsaturated aldehydes to give polyenic enol ethers with a good stereoselectivity.
