Poly(ethylene) glycols and mechanochemistry for the preparation of bioactive 3,5-disubstituted hydantoins

Abstract

Mechanochemistry was effective for the preparation of 3,5-disubstituted hydantoins from α-amino methyl esters, using either 1,1′-carbonyldiimidazole (CDI) or alkyl isocyanates.

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

“…H-Leu-OMe was used as benchmark for the mechanochemical preparation of 3-ethyl-5-isobutylhydantoin ( 2a ) (R 1 = CH 2 CH(CH 3 ) 2 and R 2 = CH 2 CH 3 , Scheme 1) [9]. The reaction was screened in the presence of various PEG additives (Table 1), by adding variable amounts of PEGs, with different molecular weights (600 < M w < 5000 Dalton) or chain end groups (dihydroxy, mono- or dimethyl ether substituents) in the second step (Table 1).…”

“…The reaction was screened in the presence of various PEG additives (Table 1), by adding variable amounts of PEGs, with different molecular weights (600 < M w < 5000 Dalton) or chain end groups (dihydroxy, mono- or dimethyl ether substituents) in the second step (Table 1). The first set of experiments was aimed to determine if the addition of variable amounts of solid MeO-PEG-2000-OMe (Table 1, entries 2–5) or HO-PEG-3400-OH (Table 1, entries 7–10) could impact both the reaction yield and rate, compared to dry-grinding conditions previously reported [9] (Table 1, entry 1). Yields were generally improved in the presence of variable amounts of PEGs (Table 1, entries 2, 3 and 7, 8), starting to decrease when reaching a critical value at 675 mg (Table 1, entries 5 and 10).…”

“…With this background, 3-ethyl-5-benzylhydantoin ( 3a ) [9] (R 1 = CH 2 Ph and R 2 = CH 2 CH 3 ) was also prepared using solid MeO-PEG-2000-OMe and HO-PEG-3400-OH as additives (Table 2). Using (L)-H-Phe-OMe .…”

“…We firstly reported the positive influence of PEG solvents as grinding agents for the mechanochemical preparation of an active pharmaceutical ingredient (API), the anticonvulsant drug ethotoin 7 [9] (marketed as Peganone ® , Scheme 1). We describe herein the impact of the addition of variable amounts of PEG, PEG chain length and end terminal groups, for the preparation of diverse 3,5-disubstituted hydantoins from α-amino methyl esters 1 , via an in situ intramolecular cyclization reaction of the ureido derivative B , which was obtained from N -carbamoylimidazole activated amino ester derivative A by reaction with various amines [9–11] (Scheme 1).…”

“…We describe herein the impact of the addition of variable amounts of PEG, PEG chain length and end terminal groups, for the preparation of diverse 3,5-disubstituted hydantoins from α-amino methyl esters 1 , via an in situ intramolecular cyclization reaction of the ureido derivative B , which was obtained from N -carbamoylimidazole activated amino ester derivative A by reaction with various amines [9–11] (Scheme 1). Hanusa’s formalism was used to represent the reaction activated by mechanochemical energy [12].…”