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

Article abstract of 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.

Full text of DOI:10.1080/07328319608002449

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Synthesis of 1-Hydroxy-10-methyl-
pyrimido [1, 6-C][1, 3]oxazine and
the Oxazepine Derivative, Structural
Mimicry of Anti-Constrained Acyclic
Thymidine
Ling-Yih Hsu a b , Dean S. Wise a b , John C. Drach a b & Leroy B.
Townsend a b
a School of Pharmacy , National Defense Medical Center , Taipei,
Taiwan , Republic of China , 107
b Department of Medicinal Chemistry, College of Pharmacy and
Department of Chemistry , The University of Michigan , Ann
Arbor, Michigan, 48109-1065
Published online: 20 Aug 2006.
To cite this article: Ling-Yih Hsu , Dean S. Wise , John C. Drach & Leroy B. Townsend (1996)
Synthesis of 1-Hydroxy-10-methyl-pyrimido [1, 6-C][1, 3]oxazine and the Oxazepine Derivative,
Structural Mimicry of Anti-Constrained Acyclic Thymidine, Nucleosides and Nucleotides, 15:9,
1481-1493, DOI: 10.1080/07328319608002449
To link to this article: http://dx.doi.org/10.1080/07328319608002449
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