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Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine

A technique for the synthesis of diethoxyphosphonomethoxy, which is applied in the field of drug synthesis, can solve the problems of long synthesis route, cumbersome operation, and high cost, and achieve the effects of reducing reaction steps, simplifying the synthesis process, and increasing the yield

Active Publication Date: 2009-12-23
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The object of the present invention is to provide a kind of synthetic method of adefovir dipivoxil intermediate 9-[2-(diethoxyphosphonomethoxy) ethyl] adenine, this method solves the long synthetic route of prior art , the problem of cumbersome operation and high cost

Method used

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  • Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine
  • Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine
  • Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine

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Embodiment 19-

[0035] The preparation of embodiment 19-[2-(diethoxyphosphonomethoxy) ethyl] adenine

[0036] Add 10.56g (0.12mol) of ethylene carbonate (0.12mol), 13.5g (0.1mol) of adenine, 0.08g of sodium hydroxide and 180ml of DMF into the reaction flask, heat to 120°C with stirring, and monitor the reaction progress by HPLC until the reaction is complete. Under the protection of an inert gas, the mixture was cooled to room temperature, 14.41 g (0.15 mol) of sodium tert-butoxide was added, and vigorously stirred while keeping the temperature of the contents at about 25°C. After the addition was completed, the temperature was maintained and stirred for 30 minutes, then cooled to 0° C., and the solution of DMF of 41.86 g (0.13 mol) of diethyl p-toluenesulfonyloxymethanephosphonate (calculated according to pure product) was started to be added dropwise. Rise to room temperature, stir, and monitor the reaction progress by HPLC until the reaction is complete. Add glacial acetic acid to adjust ...

Embodiment 29-

[0037] Preparation of Example 29-[2-(diethoxyphosphonomethoxy)ethyl]adenine

[0038] Add 9.24g (0.105mol) of ethylene carbonate (0.105mol), 13.5g (0.1mol) of adenine, 0.02g of potassium hydroxide and 180ml of DMF into the reaction flask, heat to 100°C with stirring, and monitor the reaction progress by HPLC until the reaction is complete. Under the protection of an inert gas, the mixture was cooled to 10°C, 2.4 g (0.1 mol) of sodium hydride was added, and the temperature of the contents was kept at about 10°C while stirring vigorously. After the addition was completed, the temperature was maintained and stirred for 60 minutes, then cooled to -5°C, and a DMF solution of 32.2 g (0.1 mol) (calculated as a pure product) of diethyl p-toluenesulfonyloxymethanephosphonate was started dropwise. , rise to room temperature, stir, and monitor the reaction progress by HPLC until the reaction is complete. Add hydrochloric acid to adjust the pH to 7, and stir at 20°C for 15 minutes. Conce...

Embodiment 39-

[0039] Preparation of Example 39-[2-(diethoxyphosphonomethoxy)ethyl]adenine

[0040] Add 17.6g (0.2mol) of ethylene carbonate (0.2mol), 13.5g (0.1mol) of adenine, 0.2g of sodium hydroxide and 180ml of DMF into the reaction flask, heat to 140°C with stirring, and monitor the reaction progress by HPLC until the reaction is complete. Under the protection of an inert gas, the mixture was cooled to 40°C, 22.4 g (0.2 mol) of potassium tert-butoxide was added, and vigorously stirred while keeping the temperature of the contents at about 40°C. After the addition was completed, the temperature was maintained and stirred for 30 minutes, then cooled to 5° C., and the DMF solution of 57.96 g (0.18 mol) of diethyl p-toluenesulfonyloxymethanephosphonate (calculated as pure product) was added dropwise. Rise to room temperature, stir, and monitor the reaction progress by HPLC until the reaction is complete. Sulfuric acid was added to adjust the pH to 7, and stirred at 20°C for 15 minutes. C...

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Abstract

The invention relates to a method for synthesizing adefovir dipivoxil intermediate, namely 9-[2-(diethylphosphono methoxyl)ethyl]adenine. The synthesis method comprises the following steps: (1) under the condition of alkali catalysis, adding ethylene carbonate and adenine into a solvent to perform reaction until the reaction is complete; (2) adding p-benzenesulfonyloxymethyl phosphoric acid diethylester and alkali into reaction liquid obtained in step (1) to perform reaction until the reaction is complete; and (3) performing post treatment on reaction liquid obtained in step (2) to obtain the 9-[2-(diethylphosphono methoxyl)ethyl]adenine. The synthesis method has few reaction steps, simplified operation, easy amplification and environmental protection, improves yield and greatly reduces cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing 9-[(2-diethoxyphosphonomethoxy)ethyl]adenine, an important intermediate of adefovir dipivoxil. Background technique [0002] Hepatitis B is a major disease that seriously threatens the health of our people. At present, about 120 million people in my country are carriers of hepatitis B virus, and tens of millions of patients have clinical symptoms. Currently, there are not many clinically effective anti-HBV drugs. [0003] Adefovir dipivoxil (Adefovir dipivoxil) is developed by the Gilead company of the United States. In September 2002, the FDA approved a new drug for the treatment of hepatitis B. This is the first new drug for the treatment of chronic hepatitis B approved by the FDA in recent years. After oral administration, defovir dipivoxil is rapidly converted into adefovir (Adefovir) in the body to exert antiviral effect. Clinical research results sh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 刘文峥孟洪光王国成徐奕楠
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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