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Method for producing adefovir

A product, paraformaldehyde technology, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic compounds/hydrides/coordination complex catalysts, etc., can solve the difficulties in separation and purification to achieve production Problems such as large scale, low solvent recycling rate, and large pollution safety hazards have achieved the effects of reducing the burden of medication, low cost, and easy operation

Active Publication Date: 2010-09-01
湖南欧亚药业有限公司
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  • Abstract
  • Description
  • Claims
  • 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

[0033] Synthesis of 1-chloro-2chloromethoxyethane

[0034] 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, detect by NMR, and obtain 121Kg of 1-chloro-2chloromethoxyethane product, Yield: 72%.

[0035] Synthesis of Isopropyl 2-Chloroethoxymethylphosphonate

[0036] (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 comp...

Embodiment 2

[0042] Synthesis of 1-chloro-2chloromethoxyethane

[0043] 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%.

[0044] Synthesis of Isopropyl 2-Chloroethoxymethylphosphonate

[0045] 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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PUM

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Abstract

The invention provides a method for industrially producing adefovir. The method has a synthesis route that: 2-chloroethanol is subjected to cholromethylation and then reacted with triisopropyl phosphite to generate side chain of adefovir; and the side chain and adenine are subjected to condensation and hydrolysis to prepare the adefovir product. The method has the advantages of simple process, easy operation, safety, environmental protection, the most basic raw materials and common agents, mild reaction conditions, low cost, high purity of the product, and industrial production. The adefovir provided by the method can be used as a raw material medicament for producing adefovir dipivoxil.

Description

technical field [0001] The invention relates to an industrial production method of adefovir, which belongs to the field of pharmaceutical chemistry. Background technique [0002] Adefovir (Adefovir, 9-(2-phosphomethoxyethyl) adenine) is a purine derivative with biological activity against hepatitis B virus, and its prodrug adefovir dipivoxil 9-[2 -[bis(pivaloyloxymethyl)phosphonomethoxy]ethyl]adenine is a new type of open-chain nucleotide developed by GileadSciences in the United States and approved by the FDA in September 2002 for the treatment of New drugs for 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, it is decomposed, and there are currently six synthetic routes, all of which use adenine as the starting material. The difference is that there is a change in the synthesis of the side chain. [0004] There are three existing in...

Claims

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Application Information

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IPC IPC(8): C07F9/6561B01J31/26
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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