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Method for synthesizing antiviral drugs cidofovir and buciclovir

A technology for antiviral drugs and compounds, which is applied in the field of synthesizing antiviral drugs, can solve the problems of difficult preparation of chiral intermediates, high cost, complicated and complicated processes, etc., and achieves an efficient synthesis method, high stereoselectivity, and easy availability of reaction raw materials. Effect

Active Publication Date: 2018-11-30
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above methods, the preparation of chiral intermediates is difficult and costly, and the process is cumbersome and complicated

Method used

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  • Method for synthesizing antiviral drugs cidofovir and buciclovir
  • Method for synthesizing antiviral drugs cidofovir and buciclovir
  • Method for synthesizing antiviral drugs cidofovir and buciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031] a Reaction conditions: the reactions were carried out on a 1a(0.05mmol),K 2 CO 3 (6 equiv, 0.3mmol, 41.4mg), K 3 Fe(CN) 6 (6 equiv, 0.3mmol, 98.7mg) and 10mol% L * . b Yield of isolated product. c Determined by chiral HPLC analysis. d Reaction temperature, at 0℃,

[0032] During the screening of reaction conditions, the effects of different chiral quinine ligands and temperature on the reaction were investigated. finalized L 2 The optimal ligand reaction temperature is 0°C.

[0033] Investigation of reaction conditions:

[0034] In the reaction bottle, the (DHQD) 2 PHAL (3.9mg, 0.005mmol), K 3 Fe(CN) 6 (49.4mg, 0.15mmol), K 2 CO 3 (20.7mg, 0.15mmol), K 2 OSo 2 (OH) 4 (0.36 mg, 0.001 mmol), MeSO 2 NH 2 (9.5 mg, 0.1 mmol) and a mixed solvent of water and tert-butanol (volume ratio 1 / 2, the same below, 2 mL) were added sequentially, and stirred at room temperature for 30 minutes. The olefin was added to the reaction mixture, and the hetero...

Embodiment 2

[0043]

[0044] In the reaction bottle, sequentially add (DHQD) 2 PHAL (3.9mg, 0.005mmol), K 3 Fe(CN) 6 (49.4mg, 0.15mmol), K 2 CO 3 (20.7mg, 0.15mmol), K 2 OSo 2 (OH) 4 (0.36mg, 0.001mmol), MeSO 2 NH 2 (9.5mg, 0.1mmol) and a mixed solvent of water and tert-butanol (1 / 2, 2mL). The mixture was stirred at room temperature for 30 minutes. The 2'-trimethylsilyl substituted 4-amino benzoyl protected cytosine was then added to the reaction mixture, and the heterogeneous slurry was stirred at 0°C for 12 hours, monitored by TLC. By adding Na 2 S 2 o 3 The reaction was quenched at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. The combined organic phase Na 2 SO 4 Dry, filter and concentrate in vacuo to give a crude oil. Then obtain white solid through column chromatography, yield 91%, 95%ee; Characterization data [α] 25 D =33.5(c=1.4, MeOD); ee value detection method: HPLC...

Embodiment 3

[0046]

[0047] In the reaction bottle, sequentially add (DHQD) 2 AQN (4.3mg, 0.005mmol), K 3 Fe(CN) 6 (49.4mg, 0.15mmol), K 2 CO 3 (20.7mg, 0.15mmol), K 2 OSo 2 (OH) 4 (0.36mg, 0.001mmol), MeSO 2 NH 2 (9.5mg, 0.1mmol) and a mixed solvent of water and tert-butanol (1 / 2, 2mL). The mixture was stirred at room temperature for 30 minutes. The 3'-triethylsilyl substituted purine was then added to the reaction mixture, and the heterogeneous slurry was stirred at 0°C for 12 hours, monitored by TLC. By adding Na 2 S 2 o 3 The reaction was quenched at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. The combined organic phase Na 2 SO 4 Dry, filter and concentrate in vacuo to give a crude oil. Then a white solid was obtained by column chromatography, yield 96%, 95% ee; characterization data [α] 25 D =43.17(c=0.99, MeOH); ee value detection method: HPLC (IE, n-hexane / 2-prop...

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Abstract

The invention relates to a method for synthesizing antiviral drugs, i.e., cidofovir and buciclovir, belonging to the field of asymmetric synthesis in organic chemistry. According to the invention, pyrimidine with position 1 substituted by an allyl group or purine with position 9 substituted by a butenyl group are used as raw materials and subjected to asymmetric dihydroxylation so as to obtain a key chiral intermediate of cidofovir or buciclovir, and then a multi-step reaction is carried out so as to obtain cidofovir or buciclovir. With such a route in the invention, the reaction raw materialsare easily available, stereoselectivity is high, and the chiral dihydroxynucleoside intermediates are obtained after the reaction, and the cidofovir and buciclovir can be smoothly obtained after multiple steps of transformation.

Description

technical field [0001] The invention relates to a method for synthesizing antiviral drugs cidofovir and buciclovir, belonging to the field of asymmetric synthesis in organic chemistry. Background technique [0002] Cidofovir (Cidofovir) is a broad-spectrum antiviral drug currently used in the treatment of AIDS human cytomegalovirus (HCMV) retinitis, as well as against cytomegalovirus (CMV), herpes simplex virus (HSV) and zoster Herpes virus (VZV) has a strong inhibitory activity. In 1996, it was approved by the FDA for the treatment of retinitis caused by cytomegalovirus in AIDS patients and administered by injection. At the same time, the activity of cidofovir S configuration is higher than that of R configuration. Buciclovir is also a newly discovered compound with anti-herpes virus, and it has been found that the activity of its R configuration is higher than that of the S configuration. [0003] The traditional synthetic method of cidofovir mainly uses R-glycidyl alco...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D473/18C07F9/6512
CPCC07D239/47C07D473/18
Inventor 谢明胜秦涛郭海明李建平王东超王海霞张齐英渠桂荣
Owner HENAN NORMAL UNIV
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