Iridium-catalyzed annulation between 1,2-diarylethanone and 3-aminopropanol toward site-specific 2,3-diaryl pyridines

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.

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“…ESI-HRMS: calcd for [M + H] + , m / z = 90.0913; found, m / z = 90.0913. The spectrometric data are consistent with literature values …”

Section: Methodssupporting

confidence: 91%

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

Dietz

Lucas

Groß

et al. 2021

Org. Process Res. Dev.

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“…At present, many of the methods available to prepare pyridines from non-activated ketones provide products bearing no further functionalisation (i.e. positions 4-6 = H), [39][40][41][42][43][44] or bearing specific substituents and substitution patterns. [45][46][47][48][49][50][51][52][53][54][55][56] In the former case, an operationally straight-forward Au-catalysed annulation of unfunctionalised pyridine rings to ketones was described by Arcadi, which proceeded by reacting ketones with propargylamine (Scheme 3a).…”

Section: Pyridinesmentioning

confidence: 99%

Ketones as strategic building blocks for the synthesis of natural product-inspired compounds

Foley

Waldmann

2022

Chem. Soc. Rev.

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“…To a solution of aminoacetaldehyde dimethyl acetal (8, 7.91 g, 75.2 mmol) in dry methanol (300 mL), prepared in an oven-dried Schlenk flask under nitrogen atmosphere, was added freshly distilled benzaldehyde (33, 7.60 mL, 75.2 mmol, 1.0 eq.) and the solution was stirred for18 h M (C11H17NO2): 195.26 g/mol. Tb: 130-138 (13 mbar) °C, Lit.…”

mentioning

confidence: 99%

Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium

Dietz¹,

Lucas²,

Groß³

et al. 2021

Preprint

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A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was investigated. The convergent strategy developed herein starts from 3-(R)-amino-1- butanol and builds up the BC ring system in 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 carboxylic acid or through aminolysis of the corresponding ester precursor. Final salt formation afforded dolutegravir sodium in 48–51% isolated yield (HPLC-purity: 99.7–99.9%) over six linear steps.<br>

show abstract

Iridium-catalyzed annulation between 1,2-diarylethanone and 3-aminopropanol toward site-specific 2,3-diaryl pyridines

Cited by 10 publications

References 54 publications

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

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

Ketones as strategic building blocks for the synthesis of natural product-inspired compounds

Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium

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