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化学进展 2022, Vol. 34 Issue (9): 1972-1981 DOI: 10.7536/PC211207 前一篇   后一篇

• 综述 •

磷酸酯类前药的合成方法与应用

龚智华1, 胡莎1, 金学平2, 余磊2, 朱园园3,*(), 古双喜1,*()   

  1. 1 武汉工程大学化工与制药学院 绿色化工过程教育部重点实验室 & 新型反应器与绿色化学工艺湖北省重点实验室 武汉 430205
    2 武汉软件工程职业学院 武汉市药物增溶工程技术研究中心 武汉 430205
    3 武汉工程大学化学与环境工程学院 武汉 430205
  • 收稿日期:2021-12-07 修回日期:2022-03-02 出版日期:2022-09-20 发布日期:2022-04-01
  • 基金资助:
    国家自然科学基金项目(21877087); 国家自然科学基金项目(22074114); 国家自然科学基金项目(20602164); 湖北省自然科学基金项目(2020CFB623); 湖北省自然科学基金项目(2021CFB556); 绿色化工过程教育部重点实验室开放基金项目(GCP20200201); 催化材料制备及应用湖北省重点实验室开放基金项目(202023504); 新型反应器与绿色化学工艺湖北省重点实验室(武汉工程大学)开放基金项目(40201002)
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Synthetic Methods and Application of Phosphoester Prodrugs

Zhihua Gong1, Sha Hu1, Xueping Jin2, Lei Yu2, Yuanyuan Zhu3(), Shuangxi Gu1()   

  1. 1 Key Laboratory for Green Chemical Process of Ministry of Education & Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology,Wuhan 430205, China
    2 Wuhan Drug Solubilization and Delivery Technology Research Center, Wuhan Vocational College of Software and Engineering,Wuhan 430205, China
    3 School of Chemistry and Environmental Engineering, Wuhan Institute of Technology,Wuhan 430205, China
  • Received:2021-12-07 Revised:2022-03-02 Online:2022-09-20 Published:2022-04-01
  • Contact: *e-mail: yyzhu531@163.com (Yuanyuan Zhu);shuangxigu@163.com (Shuangxi Gu)
  • Supported by:
    National Natural Science Foundation of China(21877087); National Natural Science Foundation of China(22074114); National Natural Science Foundation of China(20602164); Hubei Provincial Department of Education of China(2020CFB623); Hubei Provincial Department of Education of China(2021CFB556); Key Laboratory for Green Chemical Process of Ministry of Education Open Fund(GCP20200201); Hubei Key Laboratory for Processing and Application of Catalytic Materials(202023504); Hubei Key Laboratory of Novel Reactor and Green Chemical Technology (Wuhan Institute of Technology) Open Fund(40201002)

磷酸酯类前药与原药相比,不仅能够提高药物靶向性、稳定性和生物利用度,减少药物毒副作用,还能掩蔽药物不适气味、提高水溶性从而改善给药途径。含羟基药物的磷酸酯化是该类药物前药设计的重要方法之一。本文根据中心磷原子的价态和化合物结构进行分类,综述了各种P(Ⅴ)四配位分子、P(Ⅲ)三配位分子和H-亚磷酸酯类化合物作为磷酸酯化试剂在磷酸酯类前药合成方法中的研究进展,并阐述了这些磷酸酯类药物的应用,最后总结了各类磷酸酯化试剂的优势与局限,并结合连续流反应技术应用案例展望了其发展趋势。

关键词： 磷酸酯, 前药, 磷酸酯化, 合成方法

Compared with the original drugs, the phosphoester prodrugs can not only improve the targeting, stability and bioavailability of the drugs, reduce toxicity and side effects, but also mask the unpleasant odor of the drugs, improve water solubility, and provide better access to the drugs. Phosphorylation of hydroxyl-containing drugs is one of the most important methods for their prodrug design. According to different valences of central phosphorus atoms and chemical structures, the phosphorylation reagents include tetracoordinated P(Ⅴ) compounds, tricoordinated P(Ⅲ) compounds and H-phosphite esters. The advances of these reagents in the synthesis of phosphoester prodrugs were reviewed, and the applications of these prodrugs were elaborated. Finally, the advantages and limitations of various phosphorylation reagents were summarized, and the development trend was prospected based on the application cases of continuous flow reaction technology.

Contents

1 Introduction

2 Phosphorylation reagent classification

3 Synthesis method of phosphoester prodrugs

3.1 P(Ⅴ) tetracyclic molecules

3.2 P(Ⅲ) tri coordination molecules

3.3 H-phosphite compounds

4 Conclusion and outlook

Key words: phosphoesters, prodrugs, phosphorylation, synthetic methods
()
图1 代表性的磷酸酯类前药[3]
Fig. 1 Representative phosphoesters as prodrugs[3]
图2 三类磷酸化试剂[7]
Fig. 2 Three types of phosphorylation reagents[7]
图3 POCl3与羟基化合物的磷酸酯化反应[9,13,17]
Fig. 3 Phosphorylation of POCl3 with different hydroxyl-containing drugs[9,13,17]
图4 核苷的连续流磷酸酯化反应[19]
Fig. 4 Continuous-flow phosphorylation reaction of nucleoside[19]
图5 代表性氯代磷酸酯试剂
Fig. 5 Representative chlorophosphoester reagents
图6 氯代磷酸酯与羟基化合物的磷酸酯化反应[21,22]
Fig. 6 Phosphorylation reaction of chlorophosphoester with hydroxyl compounds[21,22]
图7 氟化磷酸酯与羟基化合物的磷酸酯化反应[24,25]
Fig. 7 Phosphorylation reaction of fluorophoester with hydroxyl compounds[24,25]
图8 叔丁基氯化镁活化胞苷的磷酸酯化反应[27]
Fig. 8 Phosphorylation reaction of cytidine activated by tert-butyl magnesium chloride[27]
图9 磷酸与羟基化合物的磷酸酯化反应
Fig. 9 Phosphorylation reaction of phosphoric acid with hydroxyl compounds
图10 H3PO4/P2O5体系与羟基化合物的磷酸酯化反应[32]
Fig. 10 Phosphorylation reaction of H3PO4/P2O5 system with hydroxyl compounds[32]
图11 咪唑促进的磷酸酯化反应[34]
Fig. 11 Imidazole-promoted phosphorylation reaction[34]
图12 磷酸二苄酯与2-甲氧基雌二醇的磷酸酯化反应[36]
Fig. 12 Phosphorylation reaction of dibenzyl phosphate with 2-methoxyestradiol[36]
图13 芳香基磷酸酯与拓扑昔康的磷酸酯化反应[37]
Fig. 13 Phosphorylation reaction of aromatic phosphoester with topotecan[37]
图14 焦磷酸酯与醇的酯化[38]
Fig. 14 Esterification of pyrophosphate and alcohols[38]
图15 焦磷酸酯与羟基化合物的磷酸酯化反应[39,40,43]
Fig. 15 Phosphorylation reaction of pyrophosphates with hydroxyl compounds[39,40,43]
图16 PCl3与羟基化合物的磷酸酯化反应[43⇓~45]
Fig. 16 Phosphorylation reaction of PCl3 with hydroxyl compounds[43⇓~45]
图17 亚磷酰胺与羟基化合物的磷酸酯化反应[49]
Fig. 17 Phosphorylation reaction of phosphoramidites with hydroxyl compounds[49]
图18 羟基化合物40的磷酸酯化反应[50]
Fig. 18 Phosphorylation reaction of hydroxyl compound 40[50]
图19 二叔丁基N,N-二异丙基亚磷酰胺的磷酸酯反应[52]
Fig. 19 Phosphorization reaction of di-tert-butyl N,N-diisopropylphosphoramidite with PF-00835321[52]
图20 H-亚磷酸单酯的合成[7]
Fig. 20 Synthesis of H-phosphite monoester[7]
图21 5'-胸腺嘧啶二核苷磷酸酯的合成[53]
Fig. 21 Synthesis of 5'-thymine dinucleoside phosphate[53]
图22 H-亚磷酸二苄酯与儿茶酚胺的磷酸酯化反应[62]
Fig. 22 Phosphorylation reaction of H-dibenzyl phosphite with catecholamine[62]
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摘要

磷酸酯类前药的合成方法与应用