Synthesis method of diethyl (tosyloxy)methylphosphonate

A technology of diethyl toluenesulfonyloxymethylphosphonate and p-toluenesulfonyl chloride, which is applied in the field of medicine and chemical industry, can solve the problems of cumbersome operation, many impurities, and high cost, and achieve the reduction of side reactions, high product yield, and improved Yield and Quality Effects

Active Publication Date: 2018-12-21
LEPING SAFELY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to overcome the shortcomings of high cost, serious three wastes, many impurities, poor quality and cumbersome operation in the synthesis technology

Method used

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  • Synthesis method of diethyl (tosyloxy)methylphosphonate
  • Synthesis method of diethyl (tosyloxy)methylphosphonate
  • Synthesis method of diethyl (tosyloxy)methylphosphonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate

[0035]34.5 g (1.15 mol) of paraformaldehyde, 84.8 g (0.80 mol) of sodium carbonate and 0.72 g (2.6 mmol) of tetrabutylammonium chloride were dissolved in 900 mL of water, and 138.0 g (1.0 mol) of phosphorous acid was added dropwise under good stirring For diethyl ester, the dropwise addition process was maintained at 5-10°C, the drop was completed within 4 hours, the temperature was raised to 80°C within 1.5 hours, and the temperature was kept at 80-85°C for 10 hours. After the condensation is completed, cool to below 3°C, add 217.2 g (1.14 mol) p-toluenesulfonyl chloride in small batches, keep at 3-8°C during the addition process, finish adding in 4 hours, raise the temperature to 30°C within 1.5 hours, ℃ insulation 9h. After the esterification, it was cooled to below 16°C, allowed to stand and separated, and 307.2 g of diethyl p-toluenesulfonyloxymethylphosphonate was isolated, with a yield of 95....

Embodiment 2

[0036] Example 2 Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate

[0037] 39.0 g (1.30 mol) of paraformaldehyde, 68.9 g (0.65 mol) of sodium carbonate and 2.86 g (10.5 mmol) of benzyltriethylammonium bromide were dissolved in 1800 mL of water, and 138.0 g (1.0 mol) was added dropwise under good stirring For diethyl phosphite, the dropping process was maintained at 3-8°C, the drop was completed within 5 hours, the temperature was raised to 78°C within 2.5 hours, and the temperature was kept at 78-83°C for 14 hours. After the condensation is completed, cool to below 5°C, add 247.6 g (1.30 mol) p-toluenesulfonyl chloride in small batches, keep at 5-10°C during the feeding process, finish adding in 3 hours, heat up to 48°C within 4.5 hours, and keep at 48-53 ℃ insulation 3.5h. After the esterification, it was cooled to below 18°C, allowed to stand and separated, and 302.4 g of diethyl p-toluenesulfonyloxymethylphosphonate was isolated, with a yield of 93.9% and a conte...

Embodiment 3

[0038] Example 3 Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate

[0039] 36.6 g (1.22 mol) of paraformaldehyde, 154.6 g (1.12 mol) of potassium carbonate and 3.14 g (7.0 mmol) of methyl trioctyl ammonium bromide were dissolved in 2500 mL of water, and 138.0 g (1.0 mol) was added dropwise under good stirring For diethyl phosphite, the dropping process was maintained at 0-5°C, and the drop was completed within 10 hours. The temperature was raised to 90°C within 4 hours, and kept at 90-95°C for 4 hours. After the condensation is completed, cool to below 5°C, add 257.2 g (1.35 mol) p-toluenesulfonyl chloride in small batches, keep at 5-10°C during the addition process, finish adding in 6 hours, raise the temperature to 33°C within 2.5 hours, at 33-38 ℃ insulation 4h. After the esterification, it was cooled to below 20°C, allowed to stand and separated, and 300.8 g of diethyl p-toluenesulfonyloxymethylphosphonate was isolated, with a yield of 93.4% and a content of 98....

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Abstract

The invention discloses a synthesis method of diethyl (tosyloxy)methylphosphonate. The method takes diethyl phosphite, paraformaldehyde, paratoluensulfonyl chloride, inorganic base and the like as rawmaterials, and the product is obtained by carrying out carrying out aftertreatment operations such as aqueous phase condensation, an esterification two-step reaction and layering. The method has thecharacteristics of being enough in raw materials source, low in price, high in safety of synthetic process, high in product yield, less in pollution caused by three wastes, environmentally-friendly, and the like, thus having a higher industrial value.

Description

technical field [0001] The invention relates to a method for synthesizing diethyl p-toluenesulfonyloxymethylphosphonate, which belongs to the field of medicine and chemical industry. Background technique [0002] Diethyl p-toluenesulfonyloxymethylphosphonate is an important intermediate for HIV and HBV first-line antiviral treatment drug tenofovir disoproxil fumarate, HBV treatment drug adefovir dipivoxil, CMV treatment drug cidofovir, etc. body. [0003] [0004] [0005] The currently disclosed synthetic route of diethyl p-toluenesulfonyloxymethylphosphonate generally uses toluene as a solvent, and under the catalysis of triethylamine, diethyl phosphite and paraformaldehyde undergo an addition reaction to obtain methylol diethyl phosphonate, and then directly add p-toluenesulfonyl chloride to the reaction solution for esterification, using triethylamine as an acid-binding agent. Wang Shixiao et al. (Journal of Shandong Institute of Light Industry, 2010, 24(2), 20...

Claims

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Application Information

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IPC IPC(8): C07F9/40
CPCC07F9/4006
Inventor 陈盛陶安妮潘劲松邱永勇曾纪森王一键过海斌郑土才
Owner LEPING SAFELY PHARMA
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