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Progress in Chemistry 2022, Vol. 34 Issue (9): 1972-1981 DOI: 10.7536/PC211207 Previous Articles   Next Articles

• Review •

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: Revised: Online: Published:
  • 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)
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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
Fig. 1 Representative phosphoesters as prodrugs[3]
Fig. 2 Three types of phosphorylation reagents[7]
Fig. 3 Phosphorylation of POCl3 with different hydroxyl-containing drugs[9,13,17]
Fig. 4 Continuous-flow phosphorylation reaction of nucleoside[19]
Fig. 5 Representative chlorophosphoester reagents
Fig. 6 Phosphorylation reaction of chlorophosphoester with hydroxyl compounds[21,22]
Fig. 7 Phosphorylation reaction of fluorophoester with hydroxyl compounds[24,25]
Fig. 8 Phosphorylation reaction of cytidine activated by tert-butyl magnesium chloride[27]
Fig. 9 Phosphorylation reaction of phosphoric acid with hydroxyl compounds
Fig. 10 Phosphorylation reaction of H3PO4/P2O5 system with hydroxyl compounds[32]
Fig. 11 Imidazole-promoted phosphorylation reaction[34]
Fig. 12 Phosphorylation reaction of dibenzyl phosphate with 2-methoxyestradiol[36]
Fig. 13 Phosphorylation reaction of aromatic phosphoester with topotecan[37]
Fig. 14 Esterification of pyrophosphate and alcohols[38]
Fig. 15 Phosphorylation reaction of pyrophosphates with hydroxyl compounds[39,40,43]
Fig. 16 Phosphorylation reaction of PCl3 with hydroxyl compounds[43⇓~45]
Fig. 17 Phosphorylation reaction of phosphoramidites with hydroxyl compounds[49]
Fig. 18 Phosphorylation reaction of hydroxyl compound 40[50]
Fig. 19 Phosphorization reaction of di-tert-butyl N,N-diisopropylphosphoramidite with PF-00835321[52]
Fig. 20 Synthesis of H-phosphite monoester[7]
Fig. 21 Synthesis of 5'-thymine dinucleoside phosphate[53]
Fig. 22 Phosphorylation reaction of H-dibenzyl phosphite with catecholamine[62]
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