The preparative synthetic approach to α,α-difluoro-γ-aminobutyric acid

Maksym Ya. Bugera; Andrii V. Herbeda; Karen V. Tarasenko; Ivan S. Kondratov

doi:10.24959/ophcj.20.209030

Authors

Maksym Ya. Bugera V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0003-2260-1379
Andrii V. Herbeda V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-4647-1057
Karen V. Tarasenko V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine Enamine Ltd, Ukraine https://orcid.org/0000-0003-2147-8399
Ivan S. Kondratov V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine Enamine Ltd, Ukraine https://orcid.org/0000-0003-0192-0725

DOI:

https://doi.org/10.24959/ophcj.20.209030

Keywords:

fluorine, ethyl bromodifluoroacetate, γ-aminobutyric acid, addition reaction, Curtius rearrangement

Abstract

Aim. To develop a convenient synthetic approach for the preparation of multigram amounts of 2,2-difluoro-γ-aminobutyric acid, which is pharmacologically promising analog of γ-aminobutyric acid (GABA).

Results and discussion. α,α-Difluoro-γ-aminobutyric acid (2,2-difluoro-GABA, 53 g) has been synthesized using the reaction of ethyl bromodifluoroacetate (EBDFA) addition to benzyl acrylate in the presence of copper as a key stage.

Experimental part. The reaction of EBDFA with benzyl acrylate in the presence of copper and tetramethylethylenediamine (TMEDA) was carried out; the resulting product was transformed to the target α,α-difluoro-γ-aminobutyric acid (in the form of hydrochloride) by consecutive debenzylation, Curtius rearrangement and treatment with hydrochloric acid to remove protecting groups. The synthesis was scaled up for the preparation of 53 g of α,α-difluoro-γ-aminobutyric acid. The ethyl ester of α,α-difluoro-γ-aminobutyric acid was also prepared and further transformed to 3,3-difluoropyrrolidine-2-one. The structure of the compounds synthesized was confirmed by ¹Н, ¹³C and ¹⁹F NMR spectroscopy, mass spectrometry and elemental analysis.

Conclusions. It has been shown that the synthetic approach developed can be used for the preparation of α,α-difluoro-γ-aminobutyric acid in multigram amounts. The pathway is much more convenient, cheaper and safer compared to the method earlier described.

Received: 30.07.2020

Revised: 19.08.2020

Accepted: 27.08.2020

Supporting Agencies

NASU theme «Synthesis of new fluoro- and phosphorus containing acyclic and heterocyclic analogues of natural compounds» (state registration № 0119U100611
2019 – 2021 years)

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