Synthesis of Pyrimido[1,6-c]][1,3]oxazine Derivatives As

• Main Authors: Lin Chorng Shiun, 林崇薰
• Other Authors: Hsu Linq-Yi
• Format: Others
• Language: zh-TW
• Published: 1995
• Online Access: http://ndltd.ncl.edu.tw/handle/50977688767899278456

碩士 === 國防醫學院 === 藥學研究所 === 83 === A mimicry analog of anti conformation acyclic pyrimidine nucleosides,8-amino-2,2-bis(hydroxymethyl)-9-methyl-1H,2H, 4H- pyrimido[1,6-c][1,3]oxazin-6-one,was synthesized in our laboratory and showed a slight activity against HIV(IC50=35mM). In order to optimizee the anti-HIV activity and gain a broad spectrum of structure-activity relationship of these anti conformation acyclic pyrimidine nucleosides , halogenation on the C-9 position and deletion of one of bishydroxylmethyl group of the reported active compound have been accomplished. The synthesis was performed by treating 6-mdthyl-2,4-dimethoxy- pyrimidine with 1,3-bis(benzyloxy)-2-propanone or benzyloxyacet- aldehyde to give 6-[2-(1,3-dibenzyyloxy)-2- hydroxy)propyl]methyl- 2,4-dimethoxypyrimidine and 6-[2-(1- benzyloxy-2-hydroxy)ethyl]- methyl-2,4-dimethoxypyrimidine, respecticely.The hydroxyl group of these two intermediates was converted to methylthiomethyl ether derivative by reacting with acetic anhydride in DMSO. Treatment of the ether derivatives with iodine in dry tetra- hydrofuran at room temperature furnished the cyclized product, 2,2-bis(bebzyloxymethyl-8- methoxyl-1H,2H,4H-pyrimido[1,6-c] [1,3]oxazin-6-one, and 2-benzyloxymethyl-8-methoxyl-1H,2H,4H- pyrimido[1,6-c][1,3 ]oxazin-6-one, respectively. The 8-methoxyl group was converted to an amino group by using methanolic ammonia under high pressure, followed by debenzylation with boron trichloride to give 8-amino-2,2- bis(hydroxylmethyl)-1H,2H,4H- pyrimido[1,6- c][1,3]oxazin-6-one,and 8-amino-2-hydroxylmethyl- 1H,2H,4H- pyrimido[1,6-c][1,3]oxazin-6-one, respective. Halogen- ation of 8-amino-2,2-bis(hydroxylmethyl)-1H,2H,4H-pyrimido[1,6-c] [1,3 ]oxazin-6-one and 8-amino-2-hydroxyl-methyl-1H,2H,4H-pyrimido [1,6-c][1,3]oxazin-6-one provided the target compounds.All the target compounds will send for anti-HIV and anti-cancer activity.