The dissertation is devoted to the development of preparative methods for the synthesis of building blocks based on geminal difluorocycloheptane, the study of the physicochemical properties of gem-difluorocycloalkanes, as well as the development of approaches for introducing gem-difluorocycloalkyl substituents into the molecules of heterocyclic compounds.
Convenient routes to obtain multigram quantities of all isomeric β-, γ-, and δ-functionalized gem-difluoro¬cycloheptane building blocks (ketones, amines, and carboxylic acids) were developed.
A preliminary systematic assessment was made of the effect of fluorination on key parameters of compounds in vitro: acidity/basicity (pKa), lipophilicity (LogP), water solubility (SW) and metabolic stability (as microsomal internal clearance, CLint) within homologous series functionalized
gem-difluorinated C3–C7 cycloalkanes. In addition, corresponding non-fluorinated and acyclic analogues were included in the study. Homologous series of carboxylic acids and amines (or their hydrochlorides) with a ring size from 3 to 7 with different positions of the gem-difluorinated fragment (β, γ or δ) relative to the functional group were used to measure pKa. It was found that the effect of gem-difluorination on the acidity/basicity of the studied compounds is defined mainly by the inductive effect of the fluorine atom and follows closely the trends observed previously for the acyclic counterparts. Therefore, the relative position of the CF2 moiety to the functional group (β, γ, or δ) is a crucial factor. Changes in lipophilicity followed more complex patterns and depended not only on the fluorination site but also on the ring size and even the functional group nature itself. Thus, for the cyclopropane derivatives, gem-difluorination resulted in slightly increased LogP values, whereas for other ring sizes, the fluorinated compounds were typically less lipophilic. The latter effect was least pronounced for the case of cyclobutane and was strongest for the β-difluorinated isomers (–LogP typically demonstrated the following trend: β > δ > γ). This was contrary to the acyclic analogs where the opposite tendency was established (δ > γ > β). Notably, the LogP trends were different for the two model amide series obtained from the corresponding carboxylic acids and primary amines. This means that simple models based on the additivity of functional group increments cannot provide a detailed understanding of lipophilicity trends in the gem-difluorocycloalkane series. In general, the observed aqueous solubility (Sw) was higher for the compounds with lower LogP values. However, the correlation between these two properties was far from perfect, possibly due to the crystal packing effects. With a few exceptions (compounds derived from small rings), gem-difluorination increased the solubility in water for cyclic derivatives, which is contrary to the tendency established for the acyclic series. Finally, in vitro measurements of human microsomal clearance showed that gem-difluorination did not decrease or even slightly improved metabolic stability of the corresponding cycloalkane derivatives.
The Levin "nitrogen deletion" strategy was implemented for a two-step parallel synthesis involving the reductive amination of (hetero)aromatic aldehydes with primary (het)arylmethyl ("benzyl") amines followed by nitrogen removal by the action of an anomeric amide without isolation of the intermediate secondary amines in pure form. A simple and reliable protocol compatible with an affordable industrial parallel synthesis workflow has been developed. The developed parallel synthesis setup was used for validation experiments involving 17 (hetero)aromatic aldehydes (benzene, pyridine, pyrimidine, pyrazole, triazole derivatives, etc.) in the reaction with p-fluorobenzylamine, as well as p-fluorobenzaldehyde in the reaction with 10 primary amines (benzene derivatives, isoxazole, imidazole, pyrazole, etc.) as starting compounds. Therefore, it is shown that the reaction sequence of reductive amination - "nitrogen deletion" is an effective method for the synthesis of a library of compounds, which can be formally considered as C(sp3)–C(sp3) coupling of two "benzyl" synthons (corresponding to (hetero)aromatic aldehydes and (het)arylmethylamines).
The reactivity of fluorinated building blocks in the Minisci-type reaction was studied. It is shown that the Minisci-type reaction is a promising alternative approach for late-stage selective modification of complex organic molecules. The compounds, synthesized or theoretically accessible by this approach, are of high research relevance.
