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Acyclovir tricyclic nucleoside derivative as well as synthesis method and application thereof

A technology of nucleoside derivatives and synthesis methods, which is applied in the field of acyclovir tricyclic nucleoside derivatives and their synthesis, can solve the problems of patients prone to drug resistance and large toxic and side effects, and achieve simple operation and high yield. High efficiency and good chemoselectivity

Active Publication Date: 2022-03-29
SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] People's research has found that although these drugs can inhibit the disease to a certain extent, they have the disadvantages of high toxicity and side effects, long-term medication is required, and patients are prone to develop drug resistance.

Method used

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  • Acyclovir tricyclic nucleoside derivative as well as synthesis method and application thereof
  • Acyclovir tricyclic nucleoside derivative as well as synthesis method and application thereof
  • Acyclovir tricyclic nucleoside derivative as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of Compound 2:

[0063]

[0064] The operation is as follows: Acyclovir 1 (22.5mg, 0.1mmol), Ac 2 O (95uL, 1.0mmol), AcOH (0.4mL) and 1,1,3,3-tetramethoxypropane (20uL, 0.12mmol) were sequentially added to a 25mL glass sealed tube, the cap in the sealed tube was tightly closed, and the The reaction mixture was stirred at 110° C. for 2.0 hours in a parallel reactor. After the reaction, cool to room temperature, transfer the reaction solution to a 25mL round-bottomed flask, evaporate and concentrate the reaction solution in a vacuum diaphragm pump with a rotary evaporator in a water bath at 30°C for 5min, spin the reaction solution to dryness, and pass it directly The target product was separated and purified by column chromatography, using THF as the eluent, and then evaporated and concentrated into a solid to obtain product 2 (27.0 mg, 89% yield). Yellow solid, mp: 133–135°C. 1 HNMR (500MHz, CDCl 3 :AcOH-d 4 =18:1)δ9.42–9.38(m,1H),8.94(s,1H),8.06(d,J=...

Embodiment 2

[0066] The preparation of compound 4:

[0067]

[0068] The operation is as follows: Ganciclovir 3 (25.5mg, 0.1mmol), Ac 2 O (95uL, 1.0mmol), AcOH (0.4mL) and 1,1,3,3-tetramethoxypropane (20uL, 0.12mmol) were sequentially added to a 25mL glass sealed tube, the cap in the sealed tube was tightly closed, and the The reaction mixture was stirred at 110° C. for 2.0 hours in a parallel reactor. After the reaction, cool to room temperature, transfer the reaction solution to a 25mL round-bottomed flask, evaporate and concentrate the reaction solution in a vacuum diaphragm pump with a rotary evaporator in a water bath at 30°C for 5min, spin the reaction solution to dryness, and pass it directly Separation and purification by column chromatography, with THF as the eluent, the target product was isolated, and then the target product was evaporated and concentrated into a solid to obtain product 4 (27.5 mg, 73% yield). Yellow solid, mp: 120–122°C, 1 HNMR (500MHz, CDCl 3)δ9.42(d,J=6...

Embodiment 3

[0070] The preparation of compound 6:

[0071]

[0072] The operation is as follows: Penciclovir 5 (25.3 mg, 0.1 mmol), Ac 2 O (95uL, 1.0mmol), AcOH (0.4mL) and 1,1,3,3-tetramethoxypropane (20uL, 0.12mmol) were sequentially added to a 25mL glass sealed tube, the cap in the sealed tube was tightly closed, and the The reaction mixture was stirred at 110° C. for 2.0 hours in a parallel reactor. After the reaction, cool to room temperature, transfer the reaction solution to a 25mL round-bottomed flask, evaporate and concentrate the reaction solution in a vacuum diaphragm pump with a rotary evaporator in a water bath at 30°C for 5min, spin the reaction solution to dryness, and pass it directly The target product was separated and purified by column chromatography, using THF as the eluent, and then evaporated and concentrated into a solid to obtain product 6 (32.5 mg, 87% yield). Yellow solid, mp: 111–113°C. 1 HNMR (500MHz, CDCl 3 )δ9.46(dd, J=7.1and 1.7Hz, 1H), 8.96(t, J=2.8H...

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Abstract

The invention belongs to the field of chemical synthesis, and particularly discloses acyclovir tricyclic nucleoside derivatives as well as a synthesis method and application thereof. The structural formula of the acyclovir tricyclic nucleoside derivative is shown as a compound 2, 4, 6, 7, 8 or 9, and the synthesis method of the acyclovir tricyclic nucleoside derivative specifically comprises the following steps: by taking acyclovir or ganciclovir or penciclovir and 1, 1, 3, 3-tetramethoxypropane as raw materials and taking AcOH and Ac2O as additives as solvents, reacting for 2 hours at 110 DEG C in a parallel reaction instrument to obtain the acyclovir tricyclic nucleoside derivative. A compound 2, 4 or 6 is obtained; furthermore, the compound 2 or the compound 4 or the compound 6 is used as a raw material, K2CO3 is used as an additive, methanol is used as a solvent, and a reaction is performed for 1 hour at normal temperature to obtain a compound 7, 8 or 9. The synthesis method is simple, convenient, high in yield and good in reaction selectivity. The prepared acyclovir tricyclic nucleoside derivative has certain HSV-1 virus inhibition activity, and has a certain prospect in preparation of anti-HSV-1 virus drugs.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular, it relates to acyclovir tricyclic nucleoside derivatives represented by compounds 2, 4, 6, 7, 8 and 9 and their synthesis methods and applications. Background technique [0002] Nucleoside drugs have many similarities with natural nucleosides in structure, and can be faked in vivo to act on the synthesis of proteins and nucleic acids. Viral diseases are the most difficult problems among human infectious diseases. The reason is that viruses host and reproduce in living cells, are difficult to kill and easily mutate, thus repeatedly attacking the body and eventually leading to transmission. Many nucleoside drugs are enzyme inhibitors in the process of viral replication, inhibiting the activity of viral DNA polymerase and reverse transcriptase, and intercalating into the viral DNA chain being synthesized, thereby inhibiting or terminating the synthesis of viral DNA chain and playing ...

Claims

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Application Information

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IPC IPC(8): C07D487/14A61P31/22
CPCC07D487/14A61P31/22
Inventor 孙文武吴滨邓婷婷谢宜兵马世杰黄洁
Owner SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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