The discovery of long-acting saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…73 The reaction between amino acid derivatives and isocyanates consists in the formation of the ureido derivatives as intermediates that are then cyclized to afford the hydantoin. In their work on the preparation of human β2 adrenoceptor agonists, 71 and in parallel of the synthesis already described above, Procopiou et al prepared this intermediate starting not from an isocyanate but directly from the urea of 3-iodo-aniline and ethyl chloroacetate, the cyclization occurring in the presence of NaH (Scheme 9). This alternative to the reaction with isocyanates using urea was also reported by Babaeva et al 74 They described the synthesis of oxa-and thiazolidine-1,3-diones in which they prepared in onepot the N-substituted glycine from 4-chloro or bromo-aniline and chloro acetic acid, which reacted in situ with urea at 120−130°C to afford the corresponding 1-(4-halogenophenyl)-hydantoin (Scheme 9).…”

“…73 The reaction between amino acid derivatives and isocyanates consists in the formation of the ureido derivatives as intermediates that are then cyclized to afford the hydantoin. In their work on the preparation of human β2 adrenoceptor agonists, 71 and in parallel of the synthesis already described above, Procopiou et al prepared this intermediate starting not from an isocyanate but directly from the urea of 3-iodo-aniline and ethyl chloroacetate, the cyclization occurring in the presence of NaH (Scheme 9).…”

“…The second strategy, equally effective, consisted in the N- alkylation of amines, including free N- terminal moiety of amino acids, with ethyl bromo or chloroacetate . The corresponding N- substituted glycine ethyl esters were thus obtained and then reacted with isocyanate to afford the 1-substituted hydantoins. − …”

“…3-Substituted hydantoins can be obtained by cyclization of the corresponding ureido derivatives. To synthesize these derivatives from amines, several reported procedures of these recent years involved the use of ethyl isocyanatoacetate with benzylamine or aniline derivatives. , The cyclization of these intermediates in acidic conditions afforded the 3-substituted hydantoins (Scheme ).…”

Discovery of a Rapidly Metabolized, Long-Acting β2 Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

“…11−13 Furthermore, two reviews on bronchodilators were published recently. 14,15 Our group reported on sulfonamides including GlaxoSmithKline's first candidate 9, 16 on vilanterol (4), 6 on hydantoins, 17 and on urea 18…”