A method for synthesizing antiviral drug cidofovir intermediates and buciclovir intermediates

A technology of antiviral drugs and intermediates, applied in the field of synthetic antiviral drugs, can solve the problems of cumbersome and complicated process, high cost, and difficult preparation of chiral intermediates, and achieve the effect of high stereoselectivity and easy availability of reaction raw materials

Active Publication Date: 2020-06-30
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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  • A method for synthesizing antiviral drug cidofovir intermediates and buciclovir intermediates
  • A method for synthesizing antiviral drug cidofovir intermediates and buciclovir intermediates
  • A method for synthesizing antiviral drug cidofovir intermediates and buciclovir intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031]

[0032] a Reaction conditions: the reactions were carried out on a 1a(0.05mmol),K 2 CO 3 (6equiv, 0.3mmol, 41.4mg), K 3 Fe(CN) 6 (6equiv, 0.3mmol, 98.7mg) and 10mol% L * . b Yield of isolated product. c Determined by chiral HPLC analysis. d Reaction temperature, at 0℃,

[0033] 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.

[0034] Investigation of reaction conditions:

[0035] 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 (0.36mg, 0.001mmol), 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...

Embodiment 2

[0046]

[0047] 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: HP...

Embodiment 3

[0049]

[0050] 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 obtain white solid through 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-propanol=...

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PUM

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Abstract

The invention relates to a method for synthesizing an antiviral drug cidofovir intermediate and a buciclovir intermediate, belonging to the field of asymmetric synthesis in organic chemistry. Using the allyl group substituted at the 1-position of pyrimidine or the butyl group substituted at the 9-position of purine as raw materials, the key chiral intermediate of cidofovir or buciclovir is obtained through asymmetric dihydroxylation reaction, followed by multi-step reaction Then get cidofovir or buciclovir. The route adopted in the present invention has easy-to-obtain reaction raw materials and high stereoselectivity. After the reaction, chiral dihydroxynucleoside intermediates can be obtained, and cidofovir and buciclovir can be successfully obtained after multi-step transformation.

Description

technical field [0001] The invention relates to a method for synthesizing an antiviral drug cidofovir intermediate and a buciclovir intermediate, 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 synthesis method of cidofov...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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