Synthesis technology of vidarabine monophosphate

A technology for vidarabine monophosphate and vidarabine monophosphate crude products, which is applied in the field of medicine and can solve the problems of high toxicity, high price, and high impurity content of pyridine, and achieve easy control of the process and high product purity and yield , the effect of low impurity content

Inactive Publication Date: 2017-06-20
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

Among the above-mentioned methods for preparing vidarabine monophosphate, method two is the mainstream production process of this product. The main problem is that the reaction quenching process exotherms violently, and the hydrolysis temperature is uncontrollable, resulting in high impurity content in the crude product. Content is reduced to meet the cost of Pharmacopoeia standard relatively high, and there are some problems in other methods, as the price of acetonitrile is more expensive, the toxicity of pyridine is big, and N, N-diisopropylethylamine and 4-dimethylaminopyridine Wastewater treatment is difficult, environmental protection treatment costs are high

Method used

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  • Synthesis technology of vidarabine monophosphate

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Effect test

Embodiment 1

[0023] Under the protection of nitrogen, add β-D- vidarabine (10g) and 250mL triethyl phosphate into the reaction flask, slowly add a mixed solution of pyrophosphoryl chloride 5.70mL and dichloromethane (20mL) dropwise at -40°C , After the addition, keep the low temperature reaction at -40°C for 24h. Pour the reaction solution into 150mL of ice water, and stir and hydrolyze it in an ice-water bath for 1h, add 200mL of dichloromethane, stir for 20min, and separate the organic layer after standing for 30min, and extract the aqueous phase with dichloromethane (100mL×2) , to combine the organic layers. Take the water phase, add saturated NaOH solution dropwise to adjust the pH of the solution between 2.5-3, then add 500mL ethanol dropwise, stir and crystallize at room temperature, filter, wash, and dry to obtain a crude product with a yield of 106% and a purity of 98.2%.

Embodiment 2

[0025] Under the protection of nitrogen, add β-D- vidarabine (10g), triethyl phosphate 200mL in the reaction flask, and slowly add the mixed solution of pyrophosphoryl chloride 6.25mL and dichloromethane (20mL) dropwise at -30°C , After the addition, keep the low temperature reaction at -30°C for 24h. Pour the reaction solution into 150mL of ice water, and stir and hydrolyze it in an ice-water bath for 1h, add 200mL of dichloromethane, stir for 20min, and separate the organic layer after standing for 30min, and extract the aqueous phase with dichloromethane (100mL×2) , to combine the organic layers. Take the water phase, add saturated NaOH solution dropwise to adjust the pH of the solution between 2.5-3, then add 500mL ethanol dropwise, stir and crystallize at room temperature, filter, wash, and dry to obtain a crude product with a yield of 101% and a purity of 98.1%.

Embodiment 3

[0027] Under the protection of nitrogen, add β-D- vidarabine (10g) and 180mL triethyl phosphate into the reaction flask, slowly add the mixed solution of pyrophosphoryl chloride 5.70mL and dichloromethane (20mL) dropwise at -20°C , After the addition, keep the low temperature reaction at -20°C for 24h. Pour the reaction solution into 150mL of ice water, and stir and hydrolyze it in an ice-water bath for 1h, add 200mL of dichloromethane, stir for 20min, and separate the organic layer after standing for 30min, and extract the aqueous phase with dichloromethane (100mL×2) , to combine the organic layers. Take the water phase, add saturated NaOH solution dropwise to adjust the pH of the solution between 2.5-3, then add 500mL ethanol dropwise, stir and crystallize at room temperature, filter, wash, and dry to obtain a crude product with a yield of 101% and a purity of 98.3%.

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Abstract

The invention discloses a synthesis technology of vidarabine monophosphate. The synthesis technology comprises the following steps: suspension dissolving vidarabine into an aprotic polar solvent firstly, carrying out reaction on a reactant and pyrophosphoryl chloride at low temperature, then carrying out hydrolysis quenching, regulating a pH value to 2.5-3, and precipitating the vidarabine monophosphate, wherein the purity of a crude product is 95 percent or above; and finally, carrying out recrystallization treatment on the vidarabine monophosphate to improve the purity of the vidarabine monophosphate to 99 percent or above with the maximum single impurity content controlled to be 0.2 percent or below. The synthesis technology of the invention has the advantages of high yield and less impurities and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthesis process of adenosine vidarabine monophosphate. Background technique [0002] Adenosine monophosphate is an anti-deoxyribonucleic acid (DNA) virus drug, which is clinically used to treat hepatitis B, chronic herpes virus, herpes zoster virus, vaccinia virus and a variety of animal viruses, as well as a small number of cancer-causing RNAs Viruses, etc., its pharmacological effect is because it can combine with deoxyribonucleic acid polymerase to reduce its activity, thereby inhibiting DNA synthesis. After adenosine monophosphate enters cells, it is phosphorylated to generate adenosine diphosphate and adenosine Sugar adenosine triphosphate, and the antiviral effect is mainly caused by monophosphate adenosine triphosphate, which competes with deoxyadenosine triphosphate to bind to DNA, thereby selectively inhibiting the activity of viral polymerase and reductase, Inhibi...

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 黄金文姚波谢达吴范宏胡美晨吴建越
Owner SHANGHAI INST OF TECH
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