Препаративний метод синтезу 4-(трифлуорометокси)піперидину та 4-(трифлуорометоксиметил)піперидину

Aim. To develop a convenient synthetic approach for the preparation of multigram amounts of 4-(trifluoromethoxy)-piperidine and 4-(trifluoromethoxymethyl)piperidine – promising building blocks for medicinal chemistry.Results and discussion. 4-(Trifluoromethoxy)piperidine (8.4 g) and 4-(trifluoromethoxymethyl)piperidine (12.9 g) were synthesized in 5 stages starting from 4-hydroxypiperidine (the overall yield 40 %) and 4-(hydroxymethyl)piperidine (the overall yield 13.5 %), respectively.Experimental part. The first stage of the synthetic strategy was acylation of 4-hydroxypiperidine with benzoyl chloride. N-benzoyl-4-hydroxypiperidine obtained was transformed to N-benzoyl-4-(trifluoromethoxy)piperidine in two stages using the Hiyama method (the synthesis of the corresponding S-methyl xanthate with the subsequent desulfurization/fluorination using N-bromosuccinimide and Olah’s reagent). Then the N-benzoyl group was reduced to benzyl one, which was removed using 1-chloroethyl chloroformate. The similar approach was applied to the synthesis of 4-(trifluoromethoxymethyl)piperidine starting from 4-(hydroxymethyl)piperidine. The structure and composition of the compounds synthesized were confrmed by 1Н, 13C and 19F NMR spectroscopy,mass-spectrometry and elemental analysis.Conclusions. The synthetic approach developed is a convenient method for the multigram preparation of4-(trifluoromethoxy)piperidine and 4-(trifluoromethoxymethyl)piperidine and can be used for the synthesis of other secondary amines containing the CF3O-group.Key words: fluorination; trifluoromethoxy group; xanthate; piperidine; protection groupМета. Розробити зручний синтетичний метод для одержання мультиграмових кількостей 4-(трифлуорометокси)піперидину та 4-(трифлуорометоксиметил)піперидину – перспективних будівельних блоків для медичної хімії.Результати та їх обговорення. Синтезовано 4-(трифлуорометокси)піперидин (8,4 г) та 4-(трифлуорометоксиметил)піперидин (12,9 г) у п’ять стадій, виходячи з 4-гідроксипіперидину (сумарний вихід – 40%) та 4-(гідроксиметил)піперидину (сумарний вихід – 13,5%) відповідно.Експериментальна частина. Першою стадією синтетичної стратегії було ацилювання 4-гідроксипіперидину бензоїлхлоридом. Одержаний N-бензоїл-4-гідроксипіперидин було перетворено на N-бензоїл-4-трифлуорометоксипіперидин у дві стадії з використанням методу Хіями (синтез відповідного S-метилксантату і наступні десульфуризація та флуорування з використанням N-бромосункциніміду та реагенту Ола). Далі N-бензоїльну групу було відновлено до бензильної, зняття якої проводили з використанням 1-хлороетилхлороформіату. Аналогічну схему було використано для синтезу 4-(трифлуорометоксиметил)піперидину, виходячи з 4-(гідроксиметил)піперидину. Структуру і склад синтезованих сполук доведено даними 1Н, 13C і 19F ЯМР-спектроскопії, мас-спектрометрії та елементного аналізу.Висновки. Розроблений метод є зручним підходом до синтезу мультиграмових кількостей 4-(трифлуорометокси)піперидину та 4-(трифлуорометоксиметил)піперидину та може бути використаний для синтезу інших вторинних амінів, що містять CF3O-групу.Ключові слова: флуорування; трифлуорометоксигрупа; ксантат; піперидин; захисна груп

Препаративний метод синтезу α,α-дифлуоро-γ-аміномасляної кислоти

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: 27.08.2020Мета. Розробити зручний синтетичний метод для одержання мультиграмових кількостей α,α-дифлуоро-γ-аміномасляної кислоти – фармакологічно перспективного аналога γ-аміномасляної кислоти (ГАМК).Результати та їх обговорення. Синтезовано 53 г α,α-дифлуоро-γ-аміномасляної кислоти (2,2-дифлуоро-ГАМК), використовуючи приєднання етилбромодифлуороацетату (ЕБДФА) до бензилакрилату в присутності міді як ключову реакцію.Експериментальна частина. Проведено реакцію ЕБДФА з бензилакрилатом у присутності міді та тетраметилетилендіаміну (ТМЕДА); одержаний продукт було перетворено на цільову α,α-дифлуоро-γ-аміномасляну кислоту (у вигляді гідрохлориду) шляхом послідовних реакцій дебензилювання, перегрупування Курціуса та обробки хлоридною кислотою для зняття захисних груп. Синтез було масштабовано для приготування 53 г α,α-дифлуоро-γ-аміномасляної кислоти. Одержано етиловий естер α,α-дифлуоро-γ-аміномасляної кислоти, який було перетворено на 3,3-дифлуоропіролідин-2-oн. Структуру і склад синтезованих речовин доведено даними 1Н, 13C і 19F ЯМР-спектроскопії, мас-спектрометрії та елементного аналізу.Висновки. Показано, що розроблений синтетичний шлях дозволяє одержати мультиграмові кількості α,α-дифлуоро-γ-аміномасляної кислоти та є набагато зручнішим, дешевшим і безпечнішим порівняно із раніше описаним методом.Received: 30.07.2020Revised: 19.08.2020Accepted: 27.08.202

Identification of readily available pseudo-natural products†

<jats:p>Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities.</jats:p&gt

Identification of Readily Available Pseudo-Natural Products

Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synthesis programs. We employed an improved version of the previously reported natural product fragment combination (NPFC) tool to analyze the full library of 3.5M synthetic small molecules and screening libraries from Enamine for PNP content, assessed the spatial complexity of Enamine-PNPs using the recently developed normalized Spatial Score (nSPS) and evaluated the bioactivity of a selected subset of Enamine-PNPs in the unbiased morphological cell painting assay. A major fraction (32%; 1.1 million compounds) of the Enamine library are PNPs which contain a significant number of compounds with unexpected and probably new bioactivity

Cyclobutyl-Containing Rigid Analogues of Threonine: Synthesis and Physical Chemical Properties

Hitherto unknown <i>cis</i>- and <i>trans</i>-1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained compounds can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups. p<i>K</i>_a values are noticeably different for both amino acids. According to the X-ray data the cyclobutane rings in both compounds are almost planar (the corresponding torsion angles are below 7°)

Radical Reactions of Alkyl 2‑Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)­phosphonate, [(bromodifluoromethyl)­sulfonyl]­benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na₂S₂O₄-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)­sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the p<i>K</i>_a values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit

Radical Reactions of Alkyl 2‑Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)­phosphonate, [(bromodifluoromethyl)­sulfonyl]­benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na₂S₂O₄-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)­sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the p<i>K</i>_a values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit

“Reported, but Still Unknown.” A Closer Look into 3,4-Bis- and 3,4,5-Tris(trifluoromethyl)pyrazoles

Straightforward practical synthetic approaches to 3,4-bis- and 3,4,5-tris­(trifluoromethyl)­pyrazoles have been developed. The key step of the both syntheses is a transformation of the carboxylic group in a pyrazole core into the trifluoromethyl group by sulfur tetrafluoride. The elaborated synthetic protocols allow gram-scale preparation of the target products. The obtained compounds are comprehensively characterized by means of crystallographic analysis, determination of p<i>K</i>_a values and fluorescence measurements

Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors

Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself