Synthesis and Properties of N,N′-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: XIV. N-[(Adamantan-1-yl)(phenyl)methyl]-N′-substituted Ureas and Symmetrical Bis-ureas

Synthesis and Properties of 1,3-Disubstituted Ureas Containing (Adamantan-1-yl)(phenyl)methyl Fragment Based on One-Pot Direct Adamantane Moiety Inclusion

“…The adamantylation reaction of phenylacetic acid ethyl ester proceeded into the α-position to the carbonyl group, with the obtaining of ethyl esters of (±)-(adamantane-1-yl)phenylacetic acid 3a and (±)-3,5-dimethyl-(adamantane-1-yl)phenylacetic acid 3b acids, yielding 91% and 85%, respectively (Scheme 1) [13]. Obtained adamantyl containing derivatives of phenylacetic acid ethyl ester 3a and 3b were hydrolyzed in ethylene glycol in the presence of KOH at the temperature of 190 °C [10], to produce (±)-(adamantane-1-yl)phenylacetic acid 4a and (±)-3,5-dimethyl-(adamantane-1-yl)phenylacetic acid 4b, with yields of 67% and 73%, respectively.…”

“…Using a one-stage method which excludes the use of toxic and explosive reagents [10], acting on acids 4a and 4b with equimolar amounts of diphenylphosphoryl azide (DPPA) and triethylamine in toluene medium led to (±)-1-[isocyanato(phenyl)methyl]adamantane 5a and (±)-1-[isocyanato(phenyl)methyl] -3,5-dimethyladamantane 5b, with yields of 95% and 89%, respectively. (±)-1-[Adamantyl(phenyl)methyl]amine hydrochloride 6a was obtained under mild conditions in toluene at room temperature using concentrated hydrochloric acid [14] with 60% yield (Scheme 2).…”

“…Obtained adamantyl containing derivatives of phenylacetic acid ethyl ester 3a and 3b were hydrolyzed in ethylene glycol in the presence of KOH at the temperature of 190 • C [10], to produce (±)-(adamantane-1-yl)phenylacetic acid 4a and (±)-3,5-dimethyl-(adamantane-1-yl)phenylacetic acid 4b, with yields of 67% and 73%, respectively.…”

“…The presence of closely spaced, bulk fragments of adamantyl (3,5-dimethyladamantyl) and phenyl in the structure of 1,3-disubstituted urea molecules will allow us to clarify the limiting dimensions of structures that can be used as sEH inhibitors, since the catalytical center of the enzyme is a "tunnel" of limited dimensions, with the following geometrical parameters: d(O2-H2) = 0.89 (2) Å, d(H2•••O1') = 1.78(2) Å, d(O2•••O1') = 2.6631 (11) Å, (O2-H2•••O1') = 171 (2) • , symmetry operation 1-x, 2-y, 1-z [8]. Due to various intermolecular interactions [9], including nonclassical hydrogen bonds, centrosymmetric dimers formed by the classical hydrogen bond O2-H2•••O1' form a three-dimensional crystal structure with a rather high packing density of 71.1% [10].…”

“…One of our studies was devoted to the synthesis of symmetric 1,3-disubstituted diureas containing both an adamantane fragment and an aromatic ring in the lipophilic part [10]. Compounds containing bulky lipophilic fragments can be used to study features of inhibition between soluble epoxide hydrolases of different species due to the differences in the protein structures [11].…”