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Method for preparing p-tosyloxymethyl diethyl phosphonate

A technology of toluenesulfonyloxymethyl diethyl phosphate and p-toluenesulfonyl chloride, which is applied in the field of cidofovir intermediates, can solve the problems of difficult liquid separation process, product loss and high cost, and achieves correct product structure, The effect of high yield and high purity

Active Publication Date: 2011-06-29
MICROBE EPIDEMIC DISEASE INST OF PLA MILITARY MEDICAL ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the above reaction scheme, in the synthetic method of p-toluenesulfonyloxymethyl phosphate diethyl ester, the reaction is very violent, and a spray tank reaction often occurs; in addition, the reaction uses pyridine as a solvent, which is difficult in the liquid separation process, and a large amount of Product loss, low yield, serious pollution, high cost

Method used

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  • Method for preparing p-tosyloxymethyl diethyl phosphonate
  • Method for preparing p-tosyloxymethyl diethyl phosphonate
  • Method for preparing p-tosyloxymethyl diethyl phosphonate

Examples

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Embodiment 1

[0018] In the reaction tank, add 60kg (437mol) of diethyl phosphite, 15kg (500mol) of paraformaldehyde and 101kg (1000mol) of triethylamine, and heat the above reaction mixture to 90°C under stirring. Within 30 minutes, the white slurry After 3 hours, the reaction mixture was cooled to room temperature; after adding 200 kg of DMF, it was cooled to 0° C., 96 g (500 mol) of p-toluenesulfonyl chloride was added within 5 minutes, the reaction mixture was stirred at room temperature for 16 hours, and ethyl acetate was added. 200L, filter the insoluble matter, wash the filtrate with saturated sodium bicarbonate, water and saturated sodium chloride (200L) respectively, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate, add toluene (2×250ml) to the residue and concentrate under reduced pressure, Obtained 106 kg of diethyl p-toluenesulfonyloxymethyl phosphate in the form of clear yellow oil, with a yield of 75%.

[0019] The proton nuclear magnetic spectrum data of...

Embodiment 2

[0022] In the reaction tank, add 60 kg (437 mol) of diethyl phosphite, 5 kg (166.7 mol) of paraformaldehyde and 101 kg (1000 mol) of triethylamine, and heat the above reaction mixture to 110 ° C under stirring. Within 30 minutes, a white slurry The solid becomes a clear solution, the temperature is lowered to 80°C, then 10kg (333mol) of paraformaldehyde is added, heated to 110°C under stirring, within 10 minutes, the white slurry turns into a clear solution, after 3 hours the reaction The mixture was cooled to room temperature; after adding 200 kg of DMF, it was cooled to 0°C, 96 g (500 mol) of p-toluenesulfonyl chloride was added within 5 minutes, the reaction mixture was stirred at room temperature for 16 hours, 200 L of ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed with saturated Wash with sodium bicarbonate, water and saturated sodium chloride (200L), dry over anhydrous magnesium sulfate, filter, concentrate the filtrate, add to...

Embodiment 3

[0024] In the reaction tank, add 60kg (437mol) of diethyl phosphite, 15kg (500mol) of paraformaldehyde and 101kg (1000mol) of triethylamine, and heat the above reaction mixture to 110°C under stirring. Within 30 minutes, the white slurry After 3 hours, the reaction mixture was cooled to room temperature; after adding 200 kg of tetrahydrofuran, it was cooled to 0° C., and 96 g (500 mol) of p-toluenesulfonyl chloride was added within 5 minutes; the reaction mixture was stirred at room temperature for 16 hours, and ethyl acetate was added. Ester 200L, filter out insoluble matter, wash the filtrate with saturated sodium bicarbonate, water and saturated sodium chloride (200L) respectively, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate, add toluene (2×250ml) to the residue and concentrate under reduced pressure , to obtain 100 kg of diethyl p-toluenesulfonyloxymethyl phosphate in the form of clear yellow oil, with a yield of 71%. The structure of the product...

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Abstract

The invention discloses a method for preparing p-tosyloxymethyl diethyl phosphonate. The method obtains the p-tosyloxymethyl diethyl phosphonate through the following steps: reacting diethyl phosphite and triethylamine with paraformaldehyde at a temperature of 80-110 DEG C, adding an organic solvent after the reaction is completed, cooling to 0-5 DEG C, and adding p-tosylchloride to perform a reaction. The used organic solvent is any one of N,N-dimethyl formamide, tetrahydrofuran, or dioxane, or a mixture mixed by several above solvents with a random mixing ratio. The amount of the organic solvent is 400 g organic solvent per 1 mole p-tosylchloride. The molar ratio of diethyl phosphate, triethylamine, paraformaldehyde and p-tosylchloride is 437:1000:500:500. Paraformaldehyde is added for 2-4 times. The temperature for the reaction performed after p-tosylchloride is added is room temperature, and the reaction time is 10-20 hours. The operation of the method is safe; the product has a correct structure, a high purity, and a high yield; the pollution cost is low; and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a method for a cidofovir intermediate, in particular to a method for preparing diethyl p-toluenesulfonyloxymethyl phosphate. Background technique [0002] The chemical name of cidofovir (cidofovir) is 1-[(S)-3-hydroxyl-2-(phosphonomethoxy) propyl] cytosine dihydrate, and its structural formula is as shown in formula I, which is a An acyclic nucleoside phosphate ester broad-spectrum antiviral drug. The drug was developed by Gilead (USA). The cidofovir injection was approved by the FDA in May 1996. France and Canada have also approved it for use. The trade name is Vistide, which is only for intravenous injection and is used to treat CMV retina in AIDS patients. Inflammation, especially for pox virus, the U.S. military has a strategic reserve of smallpox treatment drugs. The antiviral mechanism of the drug is that cidofovir can inhibit viral DNA polymerase, which is converted into active metabolites monophosphate, diphosphate an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 王洪权徐力昆窦媛媛丁建新王印松张东娜
Owner MICROBE EPIDEMIC DISEASE INST OF PLA MILITARY MEDICAL ACAD OF SCI
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