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目的探索与优化磷酰胺吗啉代寡核苷酸(PMO)关键中间产物7’-羟基-N-三苯甲基吗啉代核苷单体合成工艺路线和方法,使其合成更加高效与便捷,为以PMO为结构基础的反义寡核苷酸类药物研究奠定基础。方法以N4-苯甲酰基胞苷,鸟苷与5-甲基尿苷作为起始原料,经过将核糖环结构改造为吗啉环并对关键化学基团保护等步骤合成7’-羟基-N-三苯甲基吗啉代核苷单体。结果分别得到N4-苯甲酰基-7’-羟基-N-三苯甲基吗啉代胞苷、N2-苯甲酰基-7’-羟基-N-三苯甲基吗啉代鸟苷和7’-羟基-N-三苯甲基吗啉代胸苷,并对三者合成的工艺方法进行了优化,对所合成的中间体和目标物进行了结构确证。结论优化后的7’-羟基-N-三苯甲基吗啉代核苷单体合成工艺高效、便捷且适合放大制备。
Objective To explore and optimize the synthesis route and method of 7’-hydroxy-N-trityl morpholinosine monomer, which is the key intermediate of phosphoramidor morpholino oligonucleotide (PMO), making it more efficient and convenient to synthesize , Which laid the foundation for the research of antisense oligonucleotide based on PMO. Methods N4-benzoylcytidine, guanosine and 5-methyluridine were used as starting materials to synthesize 7’-hydroxy-N by the steps of converting the ribosyl ring structure to morpholine ring and protecting the key chemical groups - Trityl morpholino nucleoside monomer. As a result, N4-benzoyl-7’-hydroxy-N-tritylmorpholinocytidine, N2-benzoyl-7’-hydroxy-N-tritylmorpholinoguanidine and 7 ’-hydroxy-N-tritylmorpholinothymidine, and the synthesis of the three methods were optimized, the structure of the intermediate and the target were confirmed. Conclusion The optimized 7’-hydroxy-N-trityl morpholinosine monomer synthesis process is efficient, convenient and suitable for amplification.