磷酰胺吗啉代寡核苷酸关键中间产物的合成方法探索与工艺优化

发布时间：2019-04-03 16:00

【摘要】：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。
[Abstract]:Objective to explore and optimize the synthetic route and method of 7-hydroxy-N-triphenylmethylmorpholine nucleoside (PMO), which is the key intermediate of phosphoramide morpholine oligodeoxynucleotide (PMO), so as to make it more efficient and convenient. It lays a foundation for the study of antisense oligodeoxynucleotides (ASODN) based on PMO. Methods using N4-benzoyl cytidine, guanosine and 5-methyluridine as starting materials, 7-hydroxy-N-triphenylmethylmorpholine nucleoside monomers were synthesized by modifying the ribosomal structure to morpholine ring and protecting the key chemical groups. Results N _ 4-benzoyl-7-hydroxy-N-triphenyl-methyl-morpholine cytidine, N _ 2-benzoyl-7-hydroxy-N-triphenylmethyl-guanosine and 7-hydroxy-N-triphenyl-N-triphenylmethylmorpholine cytidine, respectively, were obtained. The synthesis process was optimized and the structures of the intermediates and target compounds were confirmed. Conclusion the optimized synthesis process of 7-hydroxy-N-triphenylmethylmorpholine nucleoside monomer is efficient, convenient and suitable for amplification.
【作者单位】：军事医学科学院微生物流行病研究所病原微生物生物安全国家重点实验室;
【基金】：国家科技重大专项资助项目(2015ZX09102022)
【分类号】：R914.5

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