Synthesis of 1-hydroxy-10-methyl-pyrimido[1,6-C][1,3]oxazine and the oxazepine derivative, structural mimicry of anti-constrained acyclic thymidine

• Published in: Nucleosides & nucleotides Vol. 15; no. 9; pp. 1481 - 1493
• Main Authors: Hsu, LY, Wise, DS, Drach, JC, Townsend, LB
• Format: Journal Article
• Language: English
• Published: NEW YORK Marcel Dekker Inc 01.09.1996
• Subjects: Biochemistry & Molecular Biology; Life Sciences & Biomedicine; Science & Technology; POTENT; INHIBITION; SEMIEMPIRICAL METHODS; NUCLEOSIDES; INVITRO; OPTIMIZATION; 2',3'-DIDEOXYNUCLEOSIDES; PARAMETERS; HIV-1 REPLICATION; VIRUS REVERSE-TRANSCRIPTASE
• ISSN: 0732-8311
• DOI: 10.1080/07328319608002449

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