SYNTHESIS OF 1-HYDROXY-10-METHYL-PYRIMIDO[1,6-C][1,3]OXAZINE AND THE OXAZEPINE DERIVATIVE, STRUCTURAL MIMICRY OF ANTI-CONSTRAINED ACYCLIC THYMIDINE

A number of pyrimido[1,6-c][1,3]oxazine and -oxazepine derivatives, mi micry analogs of anti-constrained acyclic thymidine, have been prepare d via treatment of lithiated 5,6-dimethyl-2,4-dimethoxypyrimidine with benzylchloromethyl ether or oxiran to furnish -dimethoxy-6-(1-benzylo xyethyl)-5-methylpyrimidine (2) and 2,4-dimethoxy-6-(1 -hydroxypropyl) -5-methylpyrimidine (8), respectively. Debenzylation of 2 afforded ,4- dimethoxy-6-(1-hydroxyethyl)-5-methylpyrimidine (3). Chloromethylation of 3 and 8 with paraformaldehyde and gaseous hydrogen chloride produc ed reactive chloromethyl ether intermediates which were converted to t he cyclized products 9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1,6-c][1,3]-ox azine (5) and -oxazepine (9)-6,8-dione, respectively. By using seleniu m dioxide, allylic oxidation of 5 and 9 afforded the target compounds, a racemic mixture of (+/-) 1-hydroxy-9-methyl-(1H, 2H, 4H, 7H)-pyrimi do[1,6-c][1,3]-oxazine (6) and -oxazepine (10)-6, 8-dione, respectivel y. Compounds 5, 6, 7, 9, and 10 were evaluated for activity against hu man immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). All of these compounds were inactive .