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A kind of synthetic technique of adefovir dipivoxil

A technology of adefovir dipivoxil and synthesis process, which is applied in the field of adefovir dipivoxil synthesis process, can solve the problems of complex process, complicated operation, low yield and the like, achieves improvement of reaction yield, simplification of production process, improved Yield effect

Active Publication Date: 2018-02-09
HENAN KANGDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The adefovir dipivoxil produced by the above two lines all need to be refined and purified by column chromatography or recrystallization, the process is complicated, the operation is complicated, and the yield is low

Method used

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  • A kind of synthetic technique of adefovir dipivoxil

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A synthetic technique for adefovir dipivoxil, comprising the following steps;

[0025] (1) In a clean glass kettle, first add 5L DMF, 5L N-methylpyrrolidone, 0.5L absolute ethanol, 1kgPMEA and 4.5kg chloromethyl pivalate, stir to raise the temperature to 60-70℃, add dropwise 3kg Triethylamine was added dropwise within 1 h, and after another 2.5 hours of reaction, the reaction was detected by HPLC. The amount of PMEA in the reaction solution was less than 0.5%, and the reaction was completed.

[0026] (2) Add 10L of ethyl acetate to the reaction solution, stir and dissolve at room temperature for 1 hour, filter, and wash the filter cake with 10L of ethyl acetate until white, and wash the obtained filtrate with 10L of 20% sodium chloride solution, discard the washing solution The water phase and the organic phase were dried with 1 kg of anhydrous calcium chloride for 2 h, filtered, and the calcium chloride solid was removed to obtain the filtrate.

[0027] (3) After conc...

Embodiment 2

[0029] A synthetic technique for adefovir dipivoxil, comprising the following steps;

[0030] (1) In a clean glass kettle, first add 5L DMF, 5L N-methylpyrrolidone, 0.5L absolute ethanol, 1kg PMEA and 5kg chloromethyl pivalate, stir to raise the temperature to 60-70°C, add dropwise 3kg Ethylamine was added dropwise within 1 h, and after another 3 hours of reaction, the reaction was detected by HPLC. The amount of PMEA in the reaction solution was less than 0.5%, and the reaction ended.

[0031] (2) Add 12L of ethyl acetate to the reaction liquid, stir and dissolve at room temperature for 1 hour, filter, and wash the filter cake with 12L of ethyl acetate until white, and wash the obtained filtrate with 12L of 20% sodium chloride solution, discard the washing liquid The water phase and the organic phase were dried with 1 kg of anhydrous calcium chloride for 2 h, filtered, and the calcium chloride solid was removed to obtain the filtrate.

[0032] (3) Concentrate the above filtr...

Embodiment 3

[0034] A synthetic technique for adefovir dipivoxil, comprising the following steps;

[0035] (1) In a clean glass kettle, first add 5L DMF, 8L N-methylpyrrolidone, 0.5L absolute ethanol, 1kgPMEA and 4.8kg chloromethyl pivalate, stir and heat up to 60-70°C, add 3kg Triethylamine was added dropwise within 1 h, and then reacted for 2 hours, and the reaction was detected by HPLC. The amount of PMEA in the reaction solution was less than 0.5%, and the reaction ended.

[0036] (2) Add 12L of ethyl acetate to the reaction solution, stir and dissolve at room temperature for 1 hour, filter, and wash the filter cake with 10L of ethyl acetate until white, and wash the obtained filtrate with 10L of 20% sodium chloride solution, discard the washing solution The water phase and the organic phase were dried with 1 kg of anhydrous calcium chloride for 2 h, filtered, and the calcium chloride solid was removed to obtain the filtrate.

[0037] (3) Concentrate the above filtrate under reduced p...

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Abstract

The invention discloses a synthesizing technology of adefovir dipivoxil, and belongs to the technical field of preparation of drug compositions. The synthesizing technology comprises the following processes of dissolving adefovir (PMEA) and chloromethyl pivalate in a mixed solvent formed from N,N-dimethylformamide (DMF), N-methylpyrrolidone and absolute ethyl alcohol, performing stirring, and raising the temperature to 60-70 DEG C, and then dropwise adding triethylamine for a reaction. The mixed solvent and a new feeding manner are adopted, a reaction process and a reaction condition are strictly controlled, and a column chromatography method or a recrystallization method does not need to be used for refining and purifying, so that the adefovir dipivoxil with high purity and high stability can be obtained, and the purity can achieve 99.5% or above, the mole yield achieves 52-55%, the yield is increased, the production technology is simplified, the production cycle is shortened, the cost is reduced, and the synthesizing technology has high industrial values and potential social and economic benefits.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical compounds, in particular to a synthesis process of adefovir dipivoxil. Background technique [0002] About 1.2 million people die from hepatitis B and related diseases every year in the world, and chronic hepatitis B virus carriers account for 5% of the global population. About 120 million people in my country are carriers of hepatitis B virus, and the number of patients with clinical symptoms is as high as several thousand Ten thousand. Hepatitis B remains a global health threat. There are currently two basic ways to treat chronic hepatitis B, one is immune activation therapy, such as interferon, and the other is drugs that inhibit viral replication, such as adefovir dipivoxil. [0003] Adefovir dipivoxil, whose chemical name is: 9-{[2-[[bis(pivaloyloxy)methoxy]phosphoryl]methoxy]ethyl}adenine, is an antiviral Nucleotide analogs are one of the world-recognized anti-hepatit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 孙津鸽李红德李文杰刘红坤高德瀛李志军
Owner HENAN KANGDA PHARMA
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