New production technology of diethyl (tosyloxy)methylphosphonate

A technology of diethyl toluenesulfonyloxymethylphosphonate and diethyl hydroxymethylphosphonate is applied in the field of new technology for producing diethyl p-toluenesulfonyloxymethylphosphonate, which can solve the problem of insufficient reaction, insufficient reaction, The problems of increased environmental pollution and long reaction time have achieved the effects of low cost, reduced pollution and extended service life

Inactive Publication Date: 2009-10-28
吴小峰
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AI Technical Summary

Problems solved by technology

This technique mainly has following deficiencies: (1) use formaldehyde solution, reaction is insufficient, yield is lower, and pollution is bigger; (2) reactio

Method used

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  • New production technology of diethyl (tosyloxy)methylphosphonate
  • New production technology of diethyl (tosyloxy)methylphosphonate

Examples

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Embodiment 1

[0019] Example 1: (1) Synthesis of diethyl hydroxymethylphosphonate Take 70kg of diethyl phosphite, 10kg of paraformaldehyde, and 30kg of water respectively in the reactor, start stirring, and heat up to between 50-60°C , heat preservation reaction for 2-4 hours, after the reaction is completed, drop to room temperature, continue to add 150kg of chloroform for extraction, separate the layers, separate the water layer and recycle it, and distill the organic layer under normal pressure to recycle the chloroform to obtain diethyl hydroxymethylphosphonate as the distillation residue 85kg.

[0020] (2) Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate Get 50kg water, 150kg p-toluenesulfonyl chloride, 70kg diethyl hydroxymethylphosphonate, 50kg ammonia water, heat up to 45-55°C for 8-10 hour, down to room temperature, add 300kg toluene for extraction, separate the water layer and reclaim it for mechanical use. After the toluene layer is filtered, reclaim the toluene under r...

Embodiment 2

[0021] Example 2: (1) Synthesis of diethyl hydroxymethyl phosphonate Take 100kg of diethyl phosphite, 30kg of paraformaldehyde, and 50kg of water respectively in the reactor, start stirring, and heat up to between 50-60°C , heat preservation reaction for 2-4 hours, after the reaction is completed, it is lowered to room temperature, continue to add 150kg of chloroform for extraction, separate layers, separate the water layer and recover it for mechanical use, distill the organic layer at normal pressure to recover chloroform, and obtain the distillation residue diethyl hydroxymethylphosphonic acid Ester 118kg.

[0022] (2) Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate Get 120kg water, 230kg p-toluenesulfonyl chloride, 100kg diethyl hydroxymethylphosphonate, 100kg ammonia water, heat up to 45-55°C for 8-10 hour, down to room temperature, add 350kg of toluene for extraction, separate the water layer and reclaim for use mechanically, and reclaim toluene under reduced ...

Embodiment 3

[0023] Embodiment 3: (1) Synthesis of diethyl hydroxymethyl phosphate Get 85kg of diethyl phosphite, 20kg of paraformaldehyde, and 40kg of water respectively in the reactor, start stirring, and heat up to between 50-60°C. Insulate and react for 2-4 hours, after the reaction is completed, cool down to room temperature, continue to add 150kg of chloroform for extraction, separate layers, separate the water layer and recover it for mechanical use, distill the organic layer under normal pressure to recover chloroform, and obtain 105kg of diethyl hydroxymethylphosphonate as the distillation residue .

[0024] (2) Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate Get 80kg water, 180kg p-toluenesulfonyl chloride, 85kg diethyl hydroxymethylphosphonate, 80kg ammonia water, heat up to 45-55°C for 8-10 hour, down to room temperature, add 320kg of toluene for extraction, separate the water layer and reclaim for mechanical use, and reclaim toluene under reduced pressure after the ...

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Abstract

The invention discloses a production technology of nucleoside AIDS virus resistant drug key intermediate-diethyl (tosyloxy)methylphosphonate. The diethyl (tosyloxy)methylphosphonate is mainly prepared by taking diethyl phosphite and paraformaldehyde as raw materials to react for 2-4 hours under the temperature ranging from 50 DEG C to 60 DEG C to prepare the diethyl(hydroxymethyl)phosphonate, then taking the diethyl(hydroxymethyl)phosphonate as a raw material, adding paratoluensulfonyl chloride into the diethyl(hydroxymethyl)phosphonate, taking an acid-binding agent as a catalyst to react for 8-10 hours under the temperature ranging from 45 DEG C to 55 DEG C, and then adding an organic solution to the reacted materials to extract, separate and distill. The production technology has short reaction time, high production yield coefficient and little environment pollution, and the obtained product has high purity.

Description

(1) Technical field: [0001] The invention belongs to the production process of pharmaceutical intermediates, in particular to a new process for the production of diethyl p-toluenesulfonyloxymethylphosphonate, a key intermediate of nucleoside anti-AIDS drugs. (two) background technology: [0002] Tenofovir, a new type of nucleoside anti-AIDS virus and hepatitis B virus drug, was developed by Gilead Science of the United States and approved by the FDA for marketing. my country approved the drug for clinical trials in China in December 2000. The drug was launched in 2006. Available at the end of the year. [0003] Diethyl p-toluenesulfonyloxymethylphosphonate, the key intermediate in the synthesis of tenofovir, is mainly prepared by reacting diethyl phosphite, toluene and formaldehyde at a certain temperature at present. Ethyl ester is prepared by adding sodium hydroxide as a catalyst and reacting with p-toluenesulfonyl chloride in the reaction kettle. This technique mainly ha...

Claims

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Application Information

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IPC IPC(8): C07F9/40
Inventor 吴小峰
Owner 吴小峰
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