Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon-Phosphorus Bond Construction Methodology

被引：1

作者：

Liu, Xiuping ^{[1
,2
,3
]}

Chen, Chen ^{[1
]}

Li, Muzi ^{[1
,2
,3
]}

Li, Man ^{[1
]}

Ren, Jie ^{[1
]}

Zhang, Qingwen ^{[1
]}

机构：

[1] Shanghai Inst Pharmaceut Ind Co Ltd, Div Med & Proc Chem, State Key Lab New Drug & Pharmaceut Proc, Shanghai 201203, Peoples R China

[2] Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China

[3] Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2023年 / 27卷 / 06期

关键词：

tenofovir alafenamide fumarate; methylthiomethyl ether; diphenyl phosphonate; carbon-phosphorus bond; bioactive phosphonates; ENANTIOMERIC N-(2-PHOSPHONOMETHOXYPROPYL) DERIVATIVES; DISOPROXIL FUMARATE; PYRIMIDINE-BASES; DOUBLE-BLIND; HEPATITIS-B; ACID; PURINE; ETHERS; IODOSUCCINIMIDE; PROTECTION;

D O I：

10.1021/acs.oprd.3c00070

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

Tenofoviralafenamide fumarate (TAF) is rising as a mainstay antiretroviralagent for the treatment of HIV and chronic HBV infections. A de novopractical synthesis of TAF circumventing tenofovir (PMPA) has beenaccomplished on a 7 g scale. This reimagined synthesis of TAF, inspiredby a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 11 (as acceptor) with methylthiomethyl (MTM) ether derivative 12 (as donor) in the presence of NIS/TfOHcombination as a promoter to construct the strategic carbon-phosphorusbond. This PMPA-free synthesis of TAF not only removes the intrinsicdrawbacks encountered by the PMPA-dependent commercial process butalso is beneficial to the diversification of the synthetic portfolioof TAF. Furthermore, this type of P-alkylation reactionwith defined stereochemistry could be deployed for the late-stagemodification of druglike molecules and natural products to accessvaluable phosphonate derivatives.

引用

页码：1079 / 1093

页数：15