Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium

Abstract

A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from (R)-3-amino-1-butanol and establishes the BC ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48–51% isolated yield (HPLC purity of 99.7–99.9%) over six linear steps.

Isotopic Radiolabeling of the Antiretroviral Drug [18F]Dolutegravir for Pharmacokinetic PET Imaging

“…Considering the difficulties encountered for the late-stage labeling of DTG, the strategy described for raltegravir radiosynthesis was explored [ 36 , 37 ]. Mimicking the recent synthesis of dolutegravir described by Dietz et al [ 38 ], [ 18 F]DTG can be synthesized by peptide coupling between carboxylic acid 3 and radiolabeled difluorobenzylamine [ 18 F] 2 ( Scheme 2 ). Although the radiosynthesis of [ 18 F] 2 has never been reported, p -[ 18 F]fluorobenzylamine has been extensively described in the literature [ 39 ].…”

“…Inspired by the recent work of Dietz and colleagues [ 38 ], [ 18 F]DTG was finally obtained in a last step of peptide coupling between [ 18 F] 2 and carboxylic acid 3 using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as coupling agent and diisopropylethylamine (DIPEA) in DMF ( Scheme 4 ). Compound 3 was synthesized in one-step from compound GSK3210346A [ 50 ] (see Scheme S3 in Supplementary Materials ).…”

Synthesis and Applications of Periodate for Fine Chemicals and Important Pharmaceuticals

“…The diol was cleaved avoided in a recent report by Aoyama and co-workers by direct installation of 1,2-propanediol (not depicted). 184 Another efficient route was recently published by Opatz et al 185 A similar strategy was reported for the synthesis of bosentan, among other APIs. An allylic double bond was installed by nucleophilic substitution and was subjected to dihydroxylation with catalytic amounts OsO 4 .…”

“… − Alternative routes employ the Lemieux–Johnson or ruthenium-catalyzed oxidation. ,, The use of metal catalysts for such transformations was avoided in a recent report by Aoyama and co-workers by direct installation of 1,2-propanediol (not depicted) . Another efficient route was recently published by Opatz et al…”

The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones

“…The chemistry of these heterocycles is actively developed not only for the design of biologically important compounds [ 7 , 8 , 9 ], but also for effective preparation in the industry [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 , 15 ]. At the same time, there is a need to search for new multifarious pyridone building blocks [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and convenient synthetic tools for the construction of polycyclic pyridones [ 1 , 2 , 3 , 15 ], including CH functionalization [ 26 ].…”