|
|||||
|
|
3-Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane-Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties |
|
| Authors: | Oleksandr P Demchuk Bohdan V Bobovskyi Bohdan V Vashchenko Dr Oleksandr V Hryshchuk Artem Skreminskyi Dr Anton V Chernykh Dr Viktoriia S Moskvina Dr Olga V Hordiyenko Prof?Dr Dmitriy M Volochnyuk Prof?Dr Oleksandr O Grygorenko |
| Institution: | 1. Enamine Ltd, Chervonotkatska Street 78, Ky?v, 02094 Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Ky?v, 02094 Ukraine;2. Enamine Ltd, Chervonotkatska Street 78, Ky?v, 02094 Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Ky?v, 01601 Ukraine;3. Enamine Ltd, Chervonotkatska Street 78, Ky?v, 02094 Ukraine;4. Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Ky?v, 01601 Ukraine;5. Enamine Ltd, Chervonotkatska Street 78, Ky?v, 02094 Ukraine Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Ky?v, 02094 Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Ky?v, 01601 Ukraine |
| Abstract: | Synthesis and physicochemical characterization of all possible cis- and trans-1,3-disubstituted cyclobutane-derived amines and carboxylic acids bearing mono-, di- and trifluoromethyl groups at the C-3 position is disclosed. Tetramethylammonium fluoride (TMAF)- or morpholinosulfur trifluoride (Morph-DAST)-mediated nucleophilic fluorination of appropriate cis- and trans-diastereomeric substrates was used as the key step for the preparation of CH2F- and CHF2-substituted derivatives. To obtain the corresponding cis- and trans-isomeric CF3-substituted derivatives, resolution of known 3-(trifluoromethyl)cyclobutanecarboxylic acid (obtained as a mixture of diastereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl-substituted cyclobutane-derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissociation constants (pKa) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physicochemical properties relevant to further drug discovery applications. |
| Keywords: | amines carboxylic acids cyclobutane building blocks fluorine |