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d4T-5'-hydro-ortho-phosphorous acid menthol ester and preparation method and application thereof

A technology of hydrophosphite and menthyl ester, which is applied in chemical instruments and methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as inconvenient operation, achieve short reaction time, mild reaction conditions, and short reaction steps little effect

Inactive Publication Date: 2011-10-12
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to first prepare the condensing agent chloro-2-chloro-1,3 dimethylimidazoline, and the reaction is strictly anhydrous, which brings some inconvenience to the operation

Method used

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  • d4T-5'-hydro-ortho-phosphorous acid menthol ester and preparation method and application thereof
  • d4T-5'-hydro-ortho-phosphorous acid menthol ester and preparation method and application thereof
  • d4T-5'-hydro-ortho-phosphorous acid menthol ester and preparation method and application thereof

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Embodiment 1

[0030] d4T-5'-menthyl hydrogen phosphite in the present invention is specifically synthesized and prepared by the following method:

[0031] 1) Under the protection of nitrogen, dissolve 2.24g (10mmol) d4T in 50mL of pyridine, then add 1.1eq of phosphorous acid, stir at 25°C to dissolve; under the protection of nitrogen, dissolve 11eq of pivaloyl chloride with 5mL of dichloromethane, Add dropwise to the above reaction solution under stirring, and stir at 25° C. for 5 min after the dropwise addition is complete.

[0032] 2) Under nitrogen protection, 1.2eq of menthol was dissolved in 5mL of dichloromethane, and added dropwise to the reaction solution while stirring.

[0033] 3) Under nitrogen protection, dissolve 1.5eq of pivaloyl chloride in 5mL of dichloromethane, add dropwise to the above reaction solution with stirring, and stir at 25°C for 10min.

[0034] 4) After the reaction, the solid was removed by filtration, and the filtrate was dissolved in dichloromethane after re...

Embodiment 2d4

[0036] Example 2d 4T-5'-menthyl hydrogen phosphite is tested for the anti-HIV-1IIIB virus activity of MT4 cells

[0037] MT4 cell assay d4T-5'-menthyl hydrogen phosphite sample anti-HIV activity assay method is as follows:

[0038] MT-4 cells were seeded in 96-well plates at a cell concentration of 1×10 5 cells / ml, 50 μl per well. Add 100, 10, 1, 0.1, 0.01, 0.001, 0.0001, 0.00001 ng / ml d4T-5′-menthyl hydrogen phosphite 50 μl in different wells, and then add 100 μl HIV-1 virus (100 TCID 50 ). A positive control (cell+AZT+virus), a virus control (cell+virus+culture solution) and a cell control (cell+culture solution) were set up, and the experiment was repeated 3 times. Calculate the half inhibitory concentration IC of the drug against the virus by the Reed-Muench method 50 .

[0039] The experimental results showed that d4T-5′-menthyl hydrogen phosphite had antiviral activity against MT4 / HIV-1IIIB, IC 50 It is 0.48nM, the activity is higher than the positive control drug ...

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Abstract

The invention discloses d4T-5'-hydro-ortho-phosphorous acid menthol ester and a preparation method and application thereof, relates to nucleoside hydro-ortho-phosphorous acid ester and provides d4T-5'-hydro-ortho-phosphorous acid menthol ester and a preparation method and application thereof. The d4T-5'-hydro-ortho-phosphorous acid menthol ester is a white solid and has the chemical name being 2',3'-bisdehydro-2',3'bideoxythymidine-5'-hydro-ortho-phosphorous acid menthol ester, the molecular formula being C20H32N2O6P, and the relative molecular mass being 426. The preparation method comprises the following steps of: condensing d4T and menthol with two hydroxyl groups of ortho-phosphorous acid in sequence in a basic solvent by taking pivaloyl chlorine as a condensing agent; and synthesizing d4T-5'-hydro-ortho-phosphorous acid menthol ester in a one-kettle way. The prepared d4T-5'-hydro-ortho-phosphorous acid menthol ester can restrain the activity of reverse transcriptase, is taken as an inhibitor of nucleoside reversed transcriptive enzyme, and is widely applied to the preparation of an anti-acquired immune deficiency syndrome medicament. The method has the advantages of readily available synthesis raw materials, short reaction time, less steps, mild condition and yield up to 69 percent.

Description

technical field [0001] The invention relates to nucleoside hydrogen phosphite, in particular to d4T-5'-menthyl hydrogen phosphite and its preparation method and application. Background technique [0002] Since the US Centers for Disease Control and Prevention reported AIDS to the world for the first time in 1981, the number of AIDS-infected or AIDS patients worldwide has increased year by year, and it has become the fourth leading cause of death for human beings. In 1987, Zidovudine (AZT, also known as azidothymidine), the first AIDS treatment drug, was approved for marketing. Nucleoside drugs have always been the main drugs for the clinical treatment of AIDS. This type of drug is a nucleoside reverse transcriptase inhibitor, and its research and development has always been the focus of many scientists. [0003] Clinically, long-term use of nucleoside drugs will lead to different degrees of drug resistance, and literature (1, Antonelli G, Turriziani O, et al.AIDS Res.Hum.Re...

Claims

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Application Information

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IPC IPC(8): C07F9/6558A61K31/685A61P31/18
Inventor 吴振杜斯明敖明陶蔡振世赵玉芬
Owner XIAMEN UNIV
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