Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium

Abstract

A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atomeconomical synthetic method for preparing this potent anti-HIV agent.

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

“…In the next step, 26 should be used for alkylating aminoacetaldehyde dimethyl acetal (8) to form the secondary amine 27. The reaction was performed either by heating in toluene or by stirring at r.t. in DCM in the presence of sodium iodide (Scheme 8).…”

“…All synthetic approaches to 3 that have been published before 2019 have been carefully reviewed. , Since then, four more routes were disclosed. − Most of the published syntheses follow a similar strategy, which is represented here by the hitherto most efficient approach from Micro Labs (2016) (Scheme ). The highly functionalized pyridone 7 (ring A) is constructed first, which then undergoes cyclization with ( R )-3-amino-1-butanol ( 13 ) to construct rings B and C. Deprotection of the usually protected enol and treatment with sodium hydroxide furnish dolutegravir sodium ( 15 ).…”

K2S2O8 Mediated Three‐component Radical Cascade C3 Alkylation of Quinoxalin‐2(1H)‐ones with Vinylarenes and 4‐Hydroxycoumarins/4‐Hydroxy‐6‐methyl‐2‐pyrone

“…1,3‐diketones, including 4‐hydroxycoumarins, are highly valuable scaffolds that are found ubiquitous in various natural products [29–33] . The conjugated structure, high solubility, low side effects, and minimum toxicity to mammals ease their uses as precursors for pharmacologically active compounds.…”

“…1,3-diketones, including 4-hydroxycoumarins, are highly valuable scaffolds that are found ubiquitous in various natural products. [29][30][31][32][33] The conjugated structure, high solubility, low side effects, and minimum toxicity to mammals ease their uses as precursors for pharmacologically active compounds. Versatile biological activities such as antiviral, [34] antifungal, [35,36] antibacterial, [37][38][39][40][41][42][43] anti-inflammatory, [44] antitumor, [45][46][47] antioxidant, [48,49] etc.…”

Phosphine-Catalyzed Synthesis of 3-Allyl-4-pyrones by the Tandem Reaction of Diynones and Allylic Alcohols

“…The classical approaches are the condensation cyclization reaction of the carbonyl compounds, which usually suffer from multi-step reactions or limited scope . Additionally, other alternative methods were also reported . Although the above synthetic methods have been well made to date, the development of a more facile, simple, and atom-economical methodology to prepare 4-pyrones from readily available material under metal-free conditions is highly desirable.…”