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Diethyl p-toluenesulfonyloxy methylphosphonate synthesis method

A technology of diethyl toluenesulfonyloxymethylphosphonate and diethyl hydroxymethylphosphonate is applied in the field of synthesis of diethyl p-toluenesulfonyloxymethylphosphonate, which can solve the problem of increasing cost, difficulty in Avoid problems such as excessive water content of diethyl hydroxymethyl phosphonate, and achieve the effect of saving energy consumption, reducing post-processing procedures, and high purity

Inactive Publication Date: 2016-05-04
SHANDONG JINCHENG PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is difficult to avoid the excessive moisture of diethyl hydroxymethylphosphonate, which will eat a large part of p-toluenesulfonyl chloride, increase the cost, and produce more impurities in the final product

Method used

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Experimental program
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Effect test

Embodiment 1

[0032] The synthetic method of described p-toluenesulfonyloxymethylphosphonic acid diethyl ester, comprises the steps:

[0033] (1) Add 30.0g of diethyl phosphite, 30mL of isopropanol, 1.0g of potassium carbonate and 7.8g of paraformaldehyde to a 250mL three-necked flask in sequence, raise the temperature to 84°C for reaction, and detect the reaction by GC after the completion of the reaction (raw material diphosphite The residue of ethyl ester is less than 0.2%), potassium carbonate is filtered out, the mother liquor is evaporated to recover isopropanol, and the distillation residue is diethyl hydroxymethylphosphonate;

[0034] (2) Cool down the diethyl hydroxymethylphosphonate prepared in step (1) to 0°C, add 60mL of dichloromethane and 37.3g of p-toluenesulfonyl chloride, and then add 26.4g of triethylamine dropwise. Continue to stir for 2h, heat up to 26°C and stir, TLC monitors the reaction (stop the reaction when there is no p-toluenesulfonyl chloride remaining), after t...

Embodiment 2

[0036] The synthetic method of described p-toluenesulfonyloxymethylphosphonic acid diethyl ester, comprises the steps:

[0037] (1) Add 30.0g of diethyl phosphite, 30mL of isopropanol, 1.0g of potassium carbonate and 7.8g of paraformaldehyde into a 250mL three-neck flask, heat up to 86°C for reaction, and after the reaction is complete by GC detection (raw material diethyl phosphite Esters residue is lower than 0.2%), potassium carbonate is filtered out, the mother liquor is evaporated to recover isopropanol and used mechanically, and the distillation residue is diethyl hydroxymethylphosphonate;

[0038] (2) Cool down the diethyl hydroxymethylphosphonate prepared in step (1) to 0°C, add 60mL of dichloromethane and 37.3g of p-toluenesulfonyl chloride, and then add 26.4g of triethylamine dropwise. Continue to stir for 2h, heat up to 26°C and stir, TLC monitors the reaction (stop the reaction when there is no p-toluenesulfonyl chloride remaining), after the reaction is complete, ...

Embodiment 3

[0040] The synthetic method of described p-toluenesulfonyloxymethylphosphonic acid diethyl ester, comprises the steps:

[0041] (1) Add 30.0g of diethyl phosphite, 30mL of dichloromethane, 1.0g of potassium carbonate and 8.0g of paraformaldehyde to a 250mL three-necked flask in sequence, raise the temperature to 82°C for reaction, and GC detects that the reaction is complete (the raw material phosphite di Ethyl residue is less than 0.2%), potassium carbonate is filtered out, the mother liquor is distilled out of dichloromethane for recycling, and the distillation residue is diethyl hydroxymethylphosphonate;

[0042] (2) Cool the diethyl hydroxymethylphosphonate prepared in step (1) to -1°C, add 60mL of dichloromethane and 37.3g of p-toluenesulfonyl chloride, then add 25.3g of triethylamine dropwise. Then continue to stir for 1.5h, heat up to 26°C and stir, TLC monitors the reaction (when there is no residue of p-toluenesulfonyl chloride, stop the reaction), after the reaction ...

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Abstract

The invention relates to the technical field of medicine, and specifically relates to a synthesis method of diethyl p-toluenesulfonyloxy methylphosphonate. The method comprises the following steps: (1) diethyl hydroxymethylphosphonate is synthesized, wherein diethyl phosphite, a solvent, a catalyst and paraformaldehyde are sequentially added into a reactor; heating is carried out and a reaction is allowed; filtering is carried out after the reaction; the solvent is removed through distillation, and the remaining substance is diethyl hydroxymethylphosphonate; and (2) diethyl p-toluenesulfonyloxy methylphosphonate is synthesized, wherein diethyl hydroxymethylphosphonate prepared in the step (1) is cooled; dichloromethane and p-toluenesulfonyl chloride are added; an acid binding agent is dropped in, and stirring is continuous for 1.5-2.5h after dropping; heating is carried out and a reaction is allowed; after the reaction, extraction, water washing and distillation are carried out, and the remaining substance is a crude product; and purification is carried out, such that a diethyl p-toluenesulfonyloxy methylphosphonate product is obtained. The method provided by the invention has the advantages of low energy consumption, simple product post treatment, high yield and high product purity. The yield can be higher than 80%. The purity can be higher than 99%.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthesis method of diethyl p-toluenesulfonyloxymethylphosphonate. Background technique [0002] Diethyl p-toluenesulfonyloxymethylphosphonate can not only be used for herbicides and fungicides, but also an important intermediate for the synthesis of nucleoside antiviral drugs tenofovir disoproxil and adefovir dipivoxil. The synthesis process of diethyl toluenesulfonyloxymethylphosphonate has complex reaction conditions and incomplete product purification. [0003] At present, the synthesis route of diethyl p-toluenesulfonyloxymethylphosphonate is relatively simple. With toluene as solvent, under the catalysis of triethylamine, diethyl phosphite and paraformaldehyde undergo addition reaction, and then molecular Internal rearrangement to obtain diethyl hydroxymethylphosphonate, p-toluenesulfonyl chloride is directly added to the reaction solution to...

Claims

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Application Information

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IPC IPC(8): C07F9/40
CPCC07F9/4006
Inventor 马永祥赵攀峰钱长健李珊珊李佳
Owner SHANDONG JINCHENG PHARMA & CHEM
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