Dietz Jule-Philipp, Ferenc Dorota, Jamison Timothy F, Gupton B Frank, Opatz Till
Department of Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14, Mainz 55128, Germany.
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge 02139, Massachusetts, United States.
Org Process Res Dev. 2021 Feb 11;25(4):789-798. doi: 10.1021/acs.oprd.0c00473. eCollection 2021 Apr 16.
Di--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--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(OBu) as the base for the alkylation of ()-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di--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).
研究了二丁基氧甲基膦酸酯用于制备活性药物成分替诺福韦（PMPA）的适用性。首先，开发了一种高效且简便的方法来获得结晶状的二丁基（羟甲基）膦酸酯。O-甲磺酰化反应可高产率地得到活性膦酰甲基化试剂。对于替诺福韦的合成，开发了一个两步反应序列，使用Mg(OBu)作为碱对（）-9-（2-羟丙基）腺嘌呤进行烷基化反应。随后用稀酸即可实现脱保护。（二丁氧基磷酰基）甲基甲磺酸酯是所测试的最有效的亲电试剂，在5 g规模下以72%的产率得到PMPA。所开发的方案也可用于制备乙肝药物阿德福韦（1 g规模下产率为64%）。
