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Synthesis process of adefovir dipivoxil raw medicine

A technology of adefovir dipivoxil and synthesis process, which is applied in the fields of compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, organic chemistry, etc. The problems such as low recycling rate and high pollution and safety hazards have achieved the effect of reducing the burden of medication, low cost and low price.

Active Publication Date: 2010-09-15
湖南欧亚药业有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The above processes involve the use of expensive chemical reagents to varying degrees. At the same time, the multi-step reaction uses a column separation method. The yield is low and the solvent recycling rate is low, which makes it difficult to achieve large-scale production of separation and purification, resulting in high cost. There are many wastes, large pollution and potential safety hazards.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Synthesis of 1-chloro-2chloromethoxyethane

[0038] In a 500L reaction kettle, add 115Kg of 2-chloroethanol, then slowly add 42Kg of paraformaldehyde, lower the temperature to below 10°C, and slowly introduce dry hydrogen chloride gas under stirring. After 4 hours, the paraformaldehyde is completely dissolved. Stand and separate layers, add anhydrous sodium sulfate to the organic layer to dry overnight, distill under reduced pressure, collect fractions at 78-84°C / 10.64kPa, and measure by NMR to obtain 121Kg of 1-chloro-2chloromethoxyethane product, Yield: 72%.

[0039] Synthesis of Isopropyl 2-Chloroethoxymethylphosphonate

[0040] (1) In a 500L enamel reaction kettle, add 90Kg of 1-chloro-2-chloromethoxyethane, raise the temperature to 90°C, and add 130Kg of triisopropyl phosphite dropwise within 2.5 hours. After dropping, the temperature was raised to 125-130° C. to continue the reaction for 3 hours, and the reaction of 1-chloro-2-chloromethoxyethane was basically c...

Embodiment 2

[0048] Synthesis of 1-chloro-2chloromethoxyethane

[0049] In a 500L reaction kettle, add 150Kg of 2-chloroethanol, then slowly add 56Kg of paraformaldehyde, lower the temperature to below 10°C, and slowly introduce dry hydrogen chloride gas under stirring. After 4 hours, the paraformaldehyde is completely dissolved. Stand still to separate the water layer, add 80kg of anhydrous sodium sulfate to the organic layer, dry overnight, distill under reduced pressure, collect 78~84℃ / 10.64kPa fractions, and determine by NMR to obtain 1-chloro-2chloromethoxyethyl 161Kg of alkane colorless liquid, yield: 68%.

[0050] Synthesis of Isopropyl 2-Chloroethoxymethylphosphonate

[0051] In a 500L enamel reaction kettle, add 124kg of 1-chloro-2-chloromethoxyethane, raise the temperature to 90°C, and add 190Kg of triisopropyl phosphite dropwise within two hours. After dropping, the temperature was raised to 125-130° C. to continue the reaction for 3.5 hours, and the reaction of 1-chloro-2-chl...

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Abstract

The invention provides an industrialized production and synthesis process of an adefovir dipivoxil raw medicine. The synthesis process comprises the following process routes of: reacting 2-chlorohydrin subjected to cholromethylation and triisopropyl phosphite to generate an adefovir lateral chain which is condensed and hydrolyzed with adenine to generate adefovir, and then carrying out condensation on the adefovir and chloromethyl pivalate to prepare the adefovir dipivoxil product. The invention has simple process, easy operation, safety, environment protection, mild reaction condition and high product purity, uses the most elementary raw materials and common reagents, and can be used for industrialized production. The invention is used for producing the adefovir dipivoxil raw material.

Description

technical field [0001] The invention relates to an industrial production synthesis process of adefovir dipivoxil, which belongs to the field of pharmaceutical chemistry. Background technique [0002] Adefovir is a purine derivative with biological activity against hepatitis B virus, and its prodrug adefovir dipivoxil 9-[2-[bis(pivaloyloxymethyl)phosphonomethoxy]B Base] adenine is a new type of open-chain nucleotide developed by GileadSciences in the United States. It was approved by the FDA in September 2002 as a new drug for the treatment of hepatitis B. In China, there are currently many manufacturers approved by the State Food and Drug Administration. [0003] According to the chemical structure characteristics of adefovir dipivoxil, it can be decomposed through the following three routes: the first one, using N, N'-dicyclohexyl-4-morpholine amidine as a catalyst, Adefovir dipivoxil The product is obtained by reacting Adefovir with chloromethyl pivalate; the second arti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 林开朝纵华北刘成杰
Owner 湖南欧亚药业有限公司
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