Synthesis of 3-Fluoropyrazolo[1,5- A ]Pyridines by Fluorination of Methyl Pyrazolo[1,5- A ]Pyridine-3-Carboxylates
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Synthesis of 3-fluoropyrazolo[1,5-a]pyridines by fluorination of methyl pyrazolo[1,5-a]pyridine-3-carboxylates Sabina V. Alieva1,2, Aleksey Yu. Vorob'ev1* 1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; e-mail: [email protected] 2 Novosibirsk State University, 1 Pirogova St., Novosibirsk 630090, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(7), 957–960
Submitted March 23, 2020 Accepted April 24, 2020
The reaction of methyl esters of pyrazolo[1,5-a]pyridine-2,3-dicarboxylic and 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acids with the fluorinating reagent Selectfluor gave 3-fluoropyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester and 3-fluoro-2-phenylpyrazolo[1,5-a]pyridine. Monitoring the progress of the reaction by 1H NMR spectroscopy showed the formation of an intermediate fluorinecontaining σ-complex. Keywords: pyrazolo[1,5-a]pyridines, Selectfluor, electrophilic fluorination.
the action of Selectfluor reagent12 was successfully applied to pyrazolo[1,5-a]pyridines.7,8 The aim of this work was to study the process of fluorination of 2,3-disubstituted pyrazolo[1,5-a]pyridines with N–F reagents. Pyrazolopyridines 1a,b (Scheme 1), which are easily synthesized by the reaction of dimethyl acetylenedicarboxylate or methyl 3-phenylpropiolate with pyridinium N-imine, were chosen as model compounds.13 After adding 1.2 equiv of Selectfluor reagent to pyrazolopyridine 1a,b in anhydrous MeCN, complete consumption of the fluorinating reagent was observed. Further evaporation of the reaction mixture in the presence of silica gel and subsequent purification of the resulting product by column chromatography on SiO2 led to 3-fluoropyrazolopyridines 2a,b (Scheme 1).
Pyrazolo[1,5-a]pyridines, due to being isosteric to indole and purine, as well as increased metabolic stability, are widely used in drug design. For example, they were used to obtain anti-tuberculosis drugs,1 EP1 receptor antagonists,2 kinase p38 inhibitors.3 Developed in Japan drug ibudilast, 2-methyl-1-[2-(propan-2-yl)pyrazolo-[1,5-a]pyridin-3-yl]propan-1-one, is an inhibitor of PDE4 phosphodiesterases and is used in the treatment of asthma and post-stroke conditions.4 Recently, ibudilast was considered as a promising agent for the treatment of multiple sclerosis.5 In modern medicinal chemistry, much attention is paid to the introduction of fluorine atoms into organic molecules.6 Indeed, about a quarter of new small molecule drugs approved by the FDA in 2015–2018 contain fluorine atoms. Examples of the use of fluoropyrazolo[1,5-a]pyridine scaffold in the design of drugs for the treatment of autoimmune diseases7 and PI3K-γ kinase inhibitors were reported.8 The main methods for the preparation of fluoropyrazolo[1,5-a]pyridine structures are annulation of the pyrazole ring to the derivatives of N-aminopyridinium salts2,9,10 or direct fluorination of the pyrazole ring with N–F reagents.11 It is notably that the r
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