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A kind of preparation method of improved 1-propylphosphonic acid cyclic anhydride

A technology of propyl phosphonic acid cyclic anhydride and propyl phosphonate dimethyl ester is applied in the field of preparation of polypeptide coupling agent, which can solve the problems of unsuitability for industrial production, high consumption and high energy consumption, and achieves yield and product The effect of quality improvement, distillation temperature reduction, and reaction performance improvement

Active Publication Date: 2016-03-02
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A method for obtaining 1-propylphosphonic acid cyclic anhydride by distillation, which can obtain colorless 1-propylphosphonic acid cyclic anhydride, but this method needs to consume more acetic anhydride, while generating more acetic acid, which is unfavorable for the reaction
At the same time, the content of the obtained product is not clearly stated in the patent, and the yield is still low (80%), and the distillation temperature reaches 280 o Above C, the energy consumption is too high
Not suitable for industrial production;
[0005] Simultaneously, a common cause that causes two kinds of method yields to be on the low side is that the boiling point of 1-propyl phosphonic acid cyclic anhydride is high, and viscosity is big, and itself is a syrupy or honey-like viscous liquid, stirring and stirring in the later stage of distillation difficulty
Therefore, the product cannot be completely distilled out, resulting in a low yield
At the same time, if the distillation is repeated under high temperature conditions, although the yield can be improved to a certain extent, the color of the product will obviously turn yellow

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 1-Ethyl-3-methylimidazolium tetrafluoroborate (748.3 g, 3.78 moles) and dimethyl propylphosphonate (100.4 g, 0.66 moles) were added to the flask, the stirring was turned on, and the temperature was raised to 65°C , start to add acetic anhydride (27.6 g, 0.27 mol) dropwise to control the dropping time for 2 hours, and control the temperature at 65-70 ° C; o C carry out atmospheric distillation, when the distillate is significantly reduced, change to vacuum distillation, collect 6Pa, 238-242 o Fraction of C. 196.5g of colorless viscous 1-propylphosphonic acid cyclic anhydride was obtained, the yield was 93.58%, and the purity was 99.2% ( 31 PNMR detection).

Embodiment 2

[0025] 1-Ethyl-3-methylimidazolium tetrafluoroborate (1287g, 6.5mol) and dimethyl propylphosphonate (163.5g, 1.075mol) were added to the flask, the stirring was started, the temperature was raised to 45°C, Begin dropwise addition of acetic anhydride (51g, 0.5mol) to control the dropwise addition time for 1h, and control the temperature at 45-50°C; o C carry out atmospheric distillation, when the distillate is significantly reduced, change to vacuum distillation, collect 5Pa, 238-240 o Fraction of C. 325.4g of colorless viscous 1-propylphosphonic acid cyclic anhydride was obtained, the yield was 95.14%, and the purity was 99.5% ( 31 PNMR detection).

Embodiment 3

[0027] 1-Ethyl-3-methylimidazolium tetrafluoroborate (1621.5g, 3 moles) and dimethyl propylphosphonate (95.8g, 0.63 moles) were added to the flask, the stirring was turned on, and the temperature was raised to 25°C , start to add acetic anhydride (30.6 g, 0.3 mole) dropwise to control the dropwise addition time for 3 hours, and control the temperature at 25-30 °C; o C carry out atmospheric distillation, when the distillate is significantly reduced, change to vacuum distillation, collect 10Pa, 240-243 o Fraction of C. 186.9g of colorless viscous 1-propylphosphonic acid cyclic anhydride was obtained, the yield was 93.26%, and the purity was 98.7% ( 31 PNMR detection).

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Abstract

The invention relates to an improved preparation method of 1-propylphosphoric cyclic anhydride, which comprises the following steps: 1) adding dimethylpropyl phosphate into an ionic liquid solvent while controlling the temperature at 0-80 DEG C, adding acetic anhydride at the same technical temperature within 1-3 hours, and heating to react under reflux for 1-8 hours to obtain a reaction solution, wherein the mol ratio of the ionic liquid solvent to the dimethylpropyl phosphate to the acetic anhydride is (10-15):(2.0-2.8):1; 2) after finishing refluxing, distilling the reaction solution at 80-140 DEG C under normal pressure to remove low-boiling-point substances; and 3) carrying out vacuum distillation on the distilled reaction solution at 235-260 DEG C to obtain the 1-propylphosphoric cyclic anhydride. The product prepared by the method is a colorless syrupy thick liquid; the yield is greater than or equal to 93%, and the content is 98-99.5%; and compared with the prior art, the yield and technique are greatly enhanced.

Description

technical field [0001] The present invention relates to an improved preparation method of a polypeptide coupling agent, more particularly to an improved preparation method of 1-propylphosphonic acid cyclic anhydride. Background technique [0002] 1-Propylphosphonic acid cyclic anhydride is a colorless or light yellow syrupy liquid, mainly used as a coupling agent for amide or ester formation in peptide synthesis. Compared with traditional peptide synthesis coupling agents such as DCC, DIC and EDC, it has the following advantages, and its application is more and more extensive, and it has a tendency to gradually replace DCC, DIC and EDC. [0003] Patent WO2009087084 discloses that dimethyl propyl phosphate and acetic anhydride (or propionic anhydride) are used as raw materials, and p-toluenesulfonic acid monohydrate or 85% phosphoric acid is used as a catalyst. The method of -propylphosphonic acid cyclic anhydride, but the shortcoming of this method is that the color of the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6571
CPCY02P20/54
Inventor 牟应科张忠政李新忠卢言建张国辉
Owner SHANDONG HUIHAI PHARMA & CHEM