Preparation method of vidarabine monophasphate

A vidarabine monophosphate and vidarabine monophosphate wet crude product technology, which is applied in the field of preparation of vidarabine monophosphate, can solve problems such as complex process operation, affecting product yield and final product quality, and achieve operational Simple process, low cost, high yield and high purity

Active Publication Date: 2018-03-13
HAINAN HULUWA PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is complex in process operation, and mercaptolation and hydrogenation are prone to produce by-product ammonia, which affects the yield of the product and the quality of the final product.

Method used

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  • Preparation method of vidarabine monophasphate
  • Preparation method of vidarabine monophasphate
  • Preparation method of vidarabine monophasphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of Crude Arabinosine Monophosphate:

[0032] 1. Prepare an aqueous sodium hydroxide solution with a mass fraction of 40%: add 37.5kg of purified water to a 50L reaction kettle, add 15.0kg of sodium hydroxide in portions under stirring, and stir to dissolve for later use.

[0033] 2. Add 10.0 kg of β-D-arabinoid adenosine and 100.0 kg of triethyl phosphate into a 200L reaction tank, and cool to -10°C.

[0034] 3. Add 10.2 kg of phosphorus oxychloride dropwise under stirring, control the temperature not to be higher than 0°C, and complete the dropwise addition within 3 to 5 hours; after the dropwise addition is completed, stir and react at -5°C for 90 minutes, and the TLC detection reaction reaches the end point, stop reaction.

[0035] 4. Slowly pump the reaction solution into a 500L reaction tank (filled with 150kg of purified water pre-frozen to 0°C), and control the temperature not to be higher than 15°C.

[0036] 5. Cool down to 0°C, add dropwise a 40% NaOH aqueous ...

Embodiment 2

[0049] Synthesis of Crude Arabinosine Monophosphate:

[0050] 1. Prepare an aqueous sodium hydroxide solution with a mass fraction of 40%: add 37.5kg of purified water to a 50L reaction kettle, add 15.0kg of sodium hydroxide in portions under stirring, and stir to dissolve for later use.

[0051] 2. Add 10.0 kg of β-D-arabinoid adenosine and 100.0 kg of triethyl phosphate into a 200L reaction tank, and cool to -13°C.

[0052] 3. Add 10.2 kg of phosphorus oxychloride dropwise with stirring, control the temperature not to be higher than 0°C, and complete the dropwise addition within 3 to 5 hours; after the dropwise addition is completed, stir and react at -2.5°C for 120 minutes, the TLC detection reaction reaches the end point, stop reaction.

[0053] 4. Slowly pump the reaction liquid into a 500L reaction tank (filled with 150kg of purified water pre-frozen to 1.5°C), and control the temperature not to be higher than 15°C.

[0054] 5. Cool down to 0°C, add dropwise a 40% NaOH aqueous so...

Embodiment 3

[0067] Synthesis of Crude Arabinosine Monophosphate:

[0068] 1. Prepare an aqueous sodium hydroxide solution with a mass fraction of 40%: add 37.5kg of purified water to a 50L reaction kettle, add 15.0kg of sodium hydroxide in portions under stirring, and stir to dissolve for later use.

[0069] 2. Add 10.0kg of β-D-arabinoid adenosine and 100.0kg of triethyl phosphate into a 200L reaction tank, and cool down to -15℃.

[0070] 3. Add 10.2kg phosphorus oxychloride dropwise with stirring, control the temperature not to be higher than 0℃, and complete the dripping within 3 to 5 hours; after the dripping is completed, stir and react at -0℃ for 150min, TLC detection reaction reaches the end point, stop reaction. Add 10.2kg phosphorus oxychloride dropwise with stirring, and control the temperature not to be higher than 0℃.

[0071] 4. Slowly pump the reaction liquid into a 500L reaction tank (containing 150kg of purified water pre-frozen to 2°C), and control the temperature to not higher ...

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Abstract

The invention discloses a preparation method of vidarabine monophosphate. The preparation method comprises the following two steps: crude product synthesis and crude product refining. In a crude product synthesis stage, reaction conditions are controlled severely, side reaction and production of related substances are reduced effectively, and high percent conversion of a target product is ensured.Meanwhile, because most of side products of reaction are dissolved in the reaction system and the target product is not dissolved in the reaction system basically, aftertreatment is facilitated to improve the purity of the product. The method is simple in process, high in product yield, high in purity and high in reaction selectivity; any special equipment is not used during production; and the preparation method is suitable for industrial production.

Description

Technical field [0001] The invention relates to the field of raw material medicine preparation, in particular to a preparation method of adenosine monophosphate. Background technique [0002] Arabinosine monophosphate, chemical name: 9-(β-D-arabinofuranose) adenine 5'-monophosphate, molecular formula: C 10 H 14 N 5 O 7 P·H 2 O, molecular weight: 365.26, chemical structural formula is as follows: [0003] [0004] Arabinosine monophosphate is a nucleotide antiviral drug. It is the second-generation preparation of Ara-A. It can selectively inhibit the activity of viral polymerase and nucleotide reductase and has a wide range of DNA viruses. Its inhibitory effect and its water solubility is significantly better than that of Ara-A. It is currently an effective and safe antiviral drug for the treatment of hepatitis B, especially for chronic hepatitis B. [0005] Adenosine monophosphate is an anti-deoxyribonucleic acid (DNA) virus drug. Its pharmacological action is to combine with the vi...

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 刘景萍刘全国陈克领林文君王家李党
Owner HAINAN HULUWA PHARMA GRP CO LTD
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