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A method for preparing vidarabine monophosphate by phosphorylation

A single phosphate vidarabine, vidarabine technology, applied in the field of medicine and chemical industry, can solve the problems of high cost, large environmental pollution, difficult recycling, etc., to reduce the generation of impurities, reduce pollution damage, and improve product quality. Effect

Active Publication Date: 2016-03-09
GUANGDONG XIANQIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purification methods of the first two phosphorylation methods are too troublesome and not conducive to industrial production
The third phosphorylation operation is relatively simple and convenient for industrialization, but obviously its production cost is high
Although the fourth phosphorylation method is simple in process, a large amount of pyridine and acetonitrile are needed in the process. Pyridine is expensive, highly toxic, and difficult to recycle, which makes the production process pollute the environment, cost high, and lack market competitiveness.

Method used

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  • A method for preparing vidarabine monophosphate by phosphorylation
  • A method for preparing vidarabine monophosphate by phosphorylation
  • A method for preparing vidarabine monophosphate by phosphorylation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] ①Put 100g (0.35mol) of vidarabine into the reaction flask, add 300ml of dichloromethane, protect with nitrogen gas, add 150ml of N,N-diisopropylethylamine (DIEA) dropwise, add 4-dimethylamino Pyridine (DMAP) 5g, cooled to -10°C to 5°C, and stirred.

[0028] ②Quick stirring step ①Reaction solution, slowly dropwise add 214.9g (1.4mol) of phosphorus oxychloride and 50ml of dichloromethane respectively, after the dropwise addition is completed, keep it at -10°C-5°C for 2h, after the reaction is completed, filter to obtain a solid 173.1 g.

[0029] ③Add water to the solid and stir to heat up to 60°C to dissolve, add activated carbon to decolorize, filter, cool the filtrate, keep it at -5°C-0°C for crystallization overnight, filter, rinse the wet product with purified water to obtain 113.9g of crude product, yield 89.1%.

[0030] Add 1140ml of purified water to the reaction bottle of the crude product, heat to 80°C, stir for 15 minutes, cool down to 5°C-0°C and keep warm fo...

Embodiment 2

[0032] ①Put 100g (0.35mol) of vidarabine into the reaction flask, add 300ml of dichloromethane, protect with nitrogen gas, add 200ml of N,N-diisopropylethylamine (DIEA) dropwise, add 4-dimethylamino Pyridine (DMAP) 5g, cooled to -10°C to 5°C, and stirred.

[0033] ②Quick stirring step ①Reaction solution, slowly dropwise add 161.2g (1.05mol) of phosphorus oxychloride and 50ml of dichloromethane respectively, after the dropwise addition, keep it at -5°C-0°C for 4h, after the reaction is completed, filter to obtain a solid 156.4 g.

[0034] ③Add water to the solid and stir to heat up to 90°C to dissolve, add activated carbon to decolorize, filter, cool the filtrate, keep it at -5°C-0°C for crystallization overnight, filter, rinse the wet product with purified water to obtain 117.6g of crude product, yield 92%.

[0035] Add 1170ml of purified water to the crude product in a reaction bottle, heat to 80°C, stir for 15 minutes, cool down to 5°C-0 and keep warm for 12 hours, precipi...

Embodiment 3

[0037] ① Put 80g (0.28mol) of vidarabine into the reaction flask, add 200ml of dichloromethane, pass nitrogen gas for protection, add 150ml of N,N-diisopropylethylamine (DIEA) dropwise, add 4-dimethylamino Pyridine (DMAP) 4g, cooled to -10°C to 5°C, and stirred.

[0038] ②Quick stirring step ①Reaction liquid, slowly dropwise add 214.9g (1.4mol) of phosphorus oxychloride and 40ml of dichloromethane respectively, after the dropwise addition is completed, keep it at -10°C-5°C for 2h, after the reaction is completed, filter to obtain a solid 173.1 g.

[0039] ③Add water to the solid and stir to heat up to 60°C to dissolve, add activated carbon to decolorize, filter, cool the filtrate, heat and crystallize overnight at -5°C-0°C, filter, rinse the wet product with purified water to obtain 93.63g of crude product, yield 91.4%.

[0040] Add 936ml of purified water to the crude product, heat to 80°C, stir for 15 minutes, cool down to 5°C-0°C and keep warm for 12 hours, precipitate cr...

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Abstract

The invention provides a phosphorylation method for preparing vidarabine monophosphate. The method is specifically as below: using vidarabine as a starting material; conducting phosphorylation on the material under the protection of inert gas and under the effect of catalyst; and conducting active carbon decoloration treatment to obtain a vidarabine monophosphate crude product. The process route is simple, low-cost and high-yield; and compared with the prior art, the production process has significantly reduced toxicity, and is suitable for process production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for preparing vidarabine monophosphate by phosphorylation. technical background [0002] Vidarabinemonophosphate (Am-AMP) is the monophosphate compound of vidarabine monophosphate (Ara-A), which is a synthetic adenosine antiviral drug. At present, it is mainly used for chronic viral hepatitis, herpes simplex virus, herpes zoster virus, vaccinia virus, various animal herpes viruses and a few carcinogenic RNA viruses in China. Vidarabine monophosphate has been listed in Europe, the United States, Japan and many other countries. Since the clinical dosage of adenosine vidarabine monophosphate is very large, in order to meet the needs of clinical medication, it is very necessary to develop a synthetic process for adenosine monophosphate which is suitable for industrial production. [0003] Adenosine monophosphate, its chemical name is 9-(β-D-arabino...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/20C07H1/00
Inventor 王雪志郑玉春张志生孙晔杜丽丽方谷良武春
Owner GUANGDONG XIANQIANG PHARMA
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