以6-氯嘌呤为原料合成2-氟腺嘌呤的新方法

A novel method for the synthesis of 2-fluoroadenine from 6-chloropurine

医药中间体2-氟腺嘌呤的合成主要存在3个问题:1使用易爆炸的重氮化反应;2原料成本高;3总收率不高,规模化难度大。这些问题限制了2-氟腺嘌呤的进一步广泛应用。为了解决以上问题,本文以廉价的6-氯嘌呤为原料,先用四氢吡喃基保护6-氯嘌呤9位NH;然后以二氯甲烷为溶剂,在三氟乙酸酐和四丁基硝酸铵体系作用下,以85%的收率得到6-氯-2-硝基-9-吡喃基嘌呤;继而以DMF为溶剂,和NH_4F反应,以83%的收率得到2-氟-6-氯嘌呤;最后在饱和的NH_3/CH_3OH溶液中氨解,得到2-氟腺嘌呤。共4步,总收率58%,产物及中间体的分离纯化不需要柱层析。同时考察了保护基团和反应规模对收率的影响。本方法原料廉价易得,避免使用高毒和剧毒试剂,操作安全简便,有较好的实际应用价值。

The conventional synthesis of 2-fluoroadenine suffers from dangerous diazo reaction,expensive starting materials,low total yields and small scales,which limit the further application of 2-fluoroadenine. In order to overcome the preceding problems,a new method for the synthesis of 2-fluoroadenine from more commercially available 6-chloropurine was developed. The key intermediate 6-chlro-2-nitro-9-pyranylpurine was obtained from N9-pyranyl protected 6-chloropurine with a yield of 85% in butyl ammonium nitrate and trifluoroacetic anhydride and using CH2Cl2as solvent. Then,6-chlro-2-nitro-9-pyranylpurine reacted with NH4F with a yield of 82% in DMF followed by the ammonolysis in NH3/CH3OH solution. Finally, 2-Fluoroadenine was obtained with a total yield of 58% through such a 4-step process. Chromatography was not necessary in the separating and purifying steps. The effects of protecting groups and reaction scales were investigated. The presented method avoided the toxic regents and expensive substrates and was simpler and safer,showing better practical application prospect.