.6 - Methyluracil N <sub> Of 1 </ Sub> - Substituted Derivatives Research

6-Methyluracile and derivatives are a kind of versatile heterocyclic compounds. Uraciles which is the basic components of many natural products and has the good biological activity may be used in the anti-tumor, anti-HIV, the sterilization as well as the anti-filterable pathogen and so on. It is also a kind of important synthesis intermediate of medicine and pesticide. We report a convenient method for synthesis of 6-methyluracile and seven N₁-substituted-6-methyluracile compounds by two steps from ethyl acetoacetate and ethyl carbamate, and the synthesis of N₁-[2-(aryloxy) ethoxy]-6-methyluracile, which has the good anti-HIV activity, was carried out by a process consisiting of six steps. The structures of the compounds were confirmed by IR, MS and ¹HNMR.Using zinc acetate as catalyst, acetoacetic ester which turns into the enol form in the non-polar solvent, reacted with ethyl carbamate at 140℃for 6h to give 6-methyl-2,3-dihydrogen-1,3-oxazine-2,4-dione in yield of 82.3%. Oxazinedione reacted with amine or N-substituted amine at 150-160℃for 2h to give N₁-substituted-6-methyluracile derivatives and the yield is 75%～90%.Six 2-(aryloxy)ethanol were synthesized by the reaction of phenol and chloroethanol. In the process, we has not used the phase transfer catalyst according to the literature report, but used the suitable solvent as dehydrating agent after the first condensation, improving the yield to 92%.1-[2-(Chloromethoxy)ethoxy]-4-methylbenzene were synthesized by chloro-methylation of 2-(aryloxy)ethanol with paraformaldehyde and dry hydrogen chloride, and under the optimizing reaction condition, the yield of the reaction is 90.3%.According to the classics Gabriel reaction, Using the CTAC as phase transfer catalyst, we prepared the intermediate by the reaction of 1-[2-(chloromethoxy) ethoxy]-4-methybenzene and potassium phthalimide at 50℃for 8h, and this intermediate was reduced by hydrazine hydrate in the yield of 85%.We have synthesized the N₁-{[(aryloxy)ethoxy]methyl}-6-methyluracile derivative by the reaction of 6-methyl-2,3-dihydrogen-1,3-oxazine-2,4-dione and [2-(aryloxy) ethoxy]methylamine, which can be used as anti-HIV drug. In conclusion, we have developed an efficient, inexpensive process for the synthesis of N₁-substituted-6-methyluraciles, which has good application propect.