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Synthetic method of vidarabine monophosphate

A technology of vidarabine monophosphate and synthesis method, which is applied in the field of medicine, can solve problems such as high environmental pressure, and achieve the effects of alleviating environmental pressure, alleviating odor problems, and alleviating environmental pressure

Active Publication Date: 2017-08-18
GANSU CHANGEE BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, the above-mentioned method still uses hydrogen sulfide, which is very odorous and toxic in the old process, as the reaction material, and the environmental pressure is still very high, failing to achieve green and environmentally friendly preparation of vidarabine monophosphate products.

Method used

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  • Synthetic method of vidarabine monophosphate
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  • Synthetic method of vidarabine monophosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the synthesis of intermediate 1

[0059]

[0060] Adenosine monophosphate (348g, 1.0mol) was added to 1.5L 1,4-dioxane, stirred for 10 minutes, the resulting solution was cooled to below 0-10°C, and 3.5L aqueous sodium hydroxide solution (1.0mol / L), control system temperature 5~15 ℃. The resulting mixed solution continued to stir for 30 minutes, cooled to below -15 to 0°C, and slowly added dropwise a 1,4-dioxane solution of p-toluenesulfonyl chloride (229g of toluenesulfonyl chloride dissolved in 1.0L of dioxane), During the process, the temperature of the reaction system was controlled at 0-5° C., and the stirring was continued for 18 hours after the dropwise addition was completed.

[0061] Concentrate the above solution to 4 L in a concentrator not higher than 30 degrees Celsius, add dilute hydrochloric acid to adjust the pH value to 4.0, stir well, leave it at room temperature overnight, and collect the solid by filtration to obtain 489 g of Inter...

Embodiment 2

[0062] Embodiment 2: the synthesis of intermediate 2

[0063]

[0064] Intermediate 1 (485g, 0.95mol) was added to 2L 1,4-dioxane, stirred and dissolved, the system was cooled to -15 degrees Celsius, and solid pyridinium bromide (330g, 1.03mmol, 1.08equ. ) slowly added to the system in batches, keeping the reaction temperature of the system within the range of 0-5°C.

[0065] After the addition, keep the temperature of the reaction system within the range of 0-5°C, continue to stir for 0.5 hours, add water to dilute the reaction solution to 4L, adjust the pH value to 4.0, concentrate the system volume to 3L, let it stand overnight, and collect the solid by filtration to obtain 503.1g intermediate Body 2, yield 91.2%.

Embodiment 3

[0066] Embodiment 3: the synthesis of intermediate 3

[0067]

[0068] Intermediate 2 (500g) was added into a mixed solution composed of 800 milliliters of acetic acid and 400 milliliters of acetic anhydride, the system was heated to reflux, kept stirring for 2 hours, added 400 milliliters of methanol, continued to stir for 0.5 hours, concentrated to dryness, and added ethanol ( 800 ml) was concentrated to dryness, and another 800 ml of ethanol was added to concentrate to dryness, and the obtained residue was recrystallized with water to obtain 463.7 g of solids, with a yield of 89.5%.

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Abstract

The invention provides a synthetic method of vidarabine monophosphate. The synthetic method comprises the following steps: a) making an intermediate shown as a formula (II) react with a solid sulfurizing agent and strong-acid ion exchange resin to obtain an intermediate shown as a formula (III), wherein the solid sulfurizing agent is selected from sodium sulfide, a sodium sulfide hydrate, sodium hydrosulfide or a sodium hydrosulfide hydrate; b), desulfurizing the intermediate shown as the formula (III) to obtain the vidarabine monophosphate. In the method, the intermediate shown as the formula (II) is subjected to sulfhydrylation through the solid sulfurizing agent such as the sodium sulfide, the sodium bisulfide, the sodium sulfide hydrate or the sodium hydrosulfide hydrate and the strong-acid ion exchange resin, and is desulfurized to obtain the vidarabine monophosphate, so that the use of hydrogen sulfide is avoided, and the pressure on the environment is lowered. Meanwhile, by adopting the synthetic method provided by the invention, the yield is 30 percent or more, and the purity of an obtained product is 99.8 percent or more.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a synthesis method of vidarabine monophosphate. Background technique [0002] DNA polymerase (DNA polymerase) is an important enzyme for cells to replicate DNA. It uses DNA as a replication template to replicate DNA from the 5' end to the 3' end. The main activity of DNA polymerase is to catalyze the synthesis of DNA in the presence of templates, primers, dNTPs, etc. [0003] The vidarabine monophosphate represented by formula (I) is a nucleotide antiviral drug, which can reduce its activity after being combined with the deoxyribonucleic acid polymerase of the virus, thereby inhibiting the synthesis of DNA. After adenosine monophosphate enters the cell, it undergoes phosphonation to generate adenosine diphosphate and adenosine triphosphate. Antiviral activity mainly comes from vidarabine adenosine triphosphate, vidarabine adenosine triphosphate and deoxyadenosine triphosphate competiti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/20C07H1/00
CPCC07H1/00C07H19/20
Inventor 刘飞孟伍柯瑾潘俊锋袁建成
Owner GANSU CHANGEE BIO PHARMA
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