Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

Abstract

Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7-hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4-dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1-ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locked analogues of emivirine. However, the compounds 4–6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.