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Green synthesis method of cidofovir

A technology of green synthesis and synthesis process, applied in the direction of organic chemistry methods, chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, etc., to achieve the effects of mild reaction conditions, ee value maintenance, and high yield

Pending Publication Date: 2022-06-28
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, chiral N4-benzoylcytosine diol is used as an intermediate in the synthesis of cidofovir, and there is no relevant report on the method of using carbon dioxide to participate in the synthesis

Method used

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  • Green synthesis method of cidofovir
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  • Green synthesis method of cidofovir

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Experimental program
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Effect test

Embodiment 1

[0015] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (10mmol) were mixed uniformly and added to the autoclave to replace CO 2 gas three times, then put the autoclave into a heating stirrer with a temperature of 60 ° C, and feed CO of 2 MPa 2 gas, after 24 hours of continuous reaction, the autoclave was cooled and excess gas was released, then dichloromethane was added to separate the product, and the chiral N4-benzoylcytosine diol compound was obtained by column chromatography, and its yield was 92%, ee value 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is where m=4, n=4, and X=Br.

Embodiment 2

[0017] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (35mmol) were mixed uniformly and added to the autoclave to replace CO. 2 gas three times, then put the autoclave into a heating stirrer with a temperature of 80 ° C, and feed CO 2 of 2 MPa. 2 After 18 hours of continuous reaction, the autoclave was cooled and excess gas was released, and then dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for next use, and the product was obtained by column chromatography. The chiral N4-benzoylcytosine diol compound has a yield of 84% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is where m=2, n=3, and X=OH.

Embodiment 3

[0019] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (45mmol) were mixed and added to the autoclave to replace CO. 2 gas three times, then put the autoclave into a heating stirrer with a temperature of 70 ° C, and feed 2 MPa of CO 2 gas, after 12 hours of continuous reaction, the autoclave was cooled and excess gas was released, and then dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for next use, and the product was obtained by column chromatography. The chiral N4-benzoylcytosine diol compound has a yield of 86% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is where m=6, n=2, and X=Br.

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Abstract

The invention discloses a green synthesis method of cidofovir, and the specific synthesis process of a chiral N4-benzoylcytosine diol compound comprises the following steps: uniformly mixing a chiral N4-benzoylcytosine epoxy compound, water and an ionic liquid catalyst, adding the mixture into a high-pressure reaction kettle, introducing CO2 gas, and reacting at 0-140 DEG C, and after the reaction is finished, separating the product and the ionic liquid catalyst, carrying out column chromatography on the product to obtain a chiral N4-benzoylcytosine diol compound, carrying out a series of reactions such as hydroxyl protection, phospholipidation and deprotection to synthesize the target product cidofovir, and repeatedly recycling the separated ionic liquid catalyst. The method does not need to use metal, inorganic base and other catalysts, does not need to add a large amount of solvent, is simple and convenient to operate and mild in reaction condition, and the used catalyst is ionic liquid and is relatively environment-friendly. Meanwhile, the yield of the synthesized target product is relatively high, and the ee value can be maintained.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chiral drug cidofovir, in particular to a green synthesis method of cidofovir. Background technique [0002] Cidofovir is a nucleoside analog that inhibits viral DNA polymerase and is effective against human cytomegalovirus (CMV) infection. It is a broad-spectrum drug with in vitro activity against human herpesviruses, adenoviruses, HPV, polyoma and vaccinia viruses and is currently in clinical studies with multiple potential applications. Due to the particularity of its structure, it is of great significance to synthesize cidofovir with a single configuration. In 1988, Robet et al. (Synthesis of (S)-N 1 -(3-hydroxy-2-phosphonylmethoxy)propylcytosine,(S)-HMPPC) uses chiral glyceraldehyde and cytosine as raw materials, DMF and methanol as solvents, and synthesizes the intermediate under the catalysis of cesium carbonate, and then passes through hydrogen Palladium oxide is reduced and TMSBr ...

Claims

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Application Information

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IPC IPC(8): C07F9/6512C07D239/47B01J31/02
CPCC07F9/6512C07D239/47B01J31/0284C07B2200/07
Inventor 李新娟马雪宁贾献彬
Owner HENAN NORMAL UNIV
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