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Preparation method of adefovir

A technology of ethyl and adenine, which is applied in the field of preparation of adefovir, can solve problems such as long time and unsuitable for industrial production, and achieve the effects of reducing the hazards of workers, reducing reaction time, and shortening working hours

Inactive Publication Date: 2017-01-11
天津市亨必达化学合成物有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Too long time is not suitable for industrial production

Method used

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  • Preparation method of adefovir
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  • Preparation method of adefovir

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1: A preparation method of adefovir

[0034] 20 g of 9-[2-(diethoxyphosphoryl methoxy) ethyl] adenine was added to 100 g of HBr aqueous solution with a concentration of 48%, stirred and heated to 90° C., and reacted for 5 hours. TLC detects that the reaction is complete and stops the reaction. The solution was cooled to room temperature and added water, keeping the temperature below 45°C, and neutralized with 50% sodium hydroxide to pH ≈ 2.5. A large amount of white solid precipitated, and stirring was continued for 4 hours, filtered and dried to obtain white PMEA. Purity determined by HPLC: 99.0% yield: 83%. The nuclear magnetic data of the product are as follows: 1HNMR(D 2 O)δ: 8.37(s,1H,2-H),8.35(s,1H,8-H), 4.49(t,2H,J=6.0Hz,1'-H), 3.86(t,2H,J =6.0Hz,2'-H),3.51(d,2H,J=9.0Hz,OCH 2 P).

Embodiment 2

[0035] Example 2: A preparation method of adefovir

[0036] 20 g of 9-[2-(diethoxyphosphoryl methoxy) ethyl] adenine was added to 100 g of HBr aqueous solution with a concentration of 48%, stirred and heated to 80° C., and reacted for 8 hours. TLC detects that the reaction is complete and stops the reaction. The solution was cooled to room temperature and added water, keeping the temperature below 45°C, and neutralized with 50% sodium hydroxide to pH ≈ 2.5. A large amount of white solid precipitated, and stirring was continued for 4 hours, filtered and dried to obtain white PMEA. Purity determined by HPLC: 98.7% yield: 81%.

Embodiment 3

[0037] Example 3: A preparation method of adefovir

[0038] 20 g of 9-[2-(diethoxyphosphoryl methoxy) ethyl] adenine was added to 80 g of HBr aqueous solution with a concentration of 48%, stirred and heated to 90° C., and reacted for 5 hours. TLC detects that the reaction is complete and stops the reaction. The solution was cooled to room temperature and added water, keeping the temperature below 45°C, and neutralized with 50% sodium hydroxide to pH ≈ 2.5. A large amount of white solid precipitated, and stirring was continued for 4 hours, filtered and dried to obtain white PMEA. Purity determined by HPLC: 99.4% yield: 85%.

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Abstract

The invention discloses a preparation method of adefovir. The preparation method comprises the following steps: adding 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine into a water solution of HBr, heating to carry out reactions, cooling, and adjusting the pH to 2-3.5 to precipitate white solids namely white adefovir. The preparation method has the advantages that during the hydrolysis of 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine, the step of evaporating organic solvents is eliminated, the reaction time is reduced, thus the preparation time is shortened; trimethyl iodo-silane, trimethyl bromo-silane, or trimethyl chloro-silane is replaced by a water solution of HBr, and the cost is reduced by nearly 100 to 400 yuan. Secondary solvent acetonitrile is not used, influence of pollution and solvent residue on drug quality is reduced; trimethyl bromo-silane is easy to decompose and is harmful to human body, and after HBr substitution, the harm to workers is largely reduced.

Description

Technical field [0001] The invention relates to a preparation method of adefovir, which belongs to the field of medicinal chemistry. Background technique [0002] Adefovir (PMEA, 2) is a nucleoside antiviral drug with a chemical name of 9-(2-phospho-acid methoxy) ethyl adenine. Clinical studies have shown that it is effective against hepatitis B virus (HBV) Has a significant inhibitory effect. [0003] The current method of preparing adefovir (PMEA): [0004] 1. Use 9-(2-hydroxyethyl) adenine or its N6-benzoyl derivative, use DMF as solvent and sodium hydride as catalyst to undergo condensation reaction, and then hydrolyze with trimethylsilyl iodide. Exchange column chromatography to obtain the product adefovir. [0005] [0006] 2. Carry out Arbuzov reaction with 2-acetoxyethoxy methyl chloride and triethyl phosphite. After separation, purification and halogenation by ion chromatography, it is then condensed with adenine and separated under silica gel column separation conditions t...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 李惠龙张智强王凯李连启李果任晓峰赵钊宋金津杨昕
Owner 天津市亨必达化学合成物有限公司
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