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A kind of preparation method of amino polyethylene glycol propionic acid

A technology of polyethylene glycol propionate and polyethylene glycol propionate tert-butyl, which is applied in the field of preparation of aminopolyethylene glycol propionate, and can solve the problems of high reactivity, difficulty in product separation and purification, unfavorable industrial scale-up production, etc. problems, to achieve the effect of mild reaction conditions and simple operation

Active Publication Date: 2021-03-09
JIANGSU GENSCRIPT BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses ammonium hydroxide as the ammoniating reagent, and the reactivity of the higher primary amine generated by the reaction is higher than that of the original amine, so the ammoniation reaction of this step often obtains a mixture of primary, secondary, tertiary and quaternary ammonium salts , the separation and purification of the product is difficult, which is not conducive to industrial scale-up production

Method used

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  • A kind of preparation method of amino polyethylene glycol propionic acid
  • A kind of preparation method of amino polyethylene glycol propionic acid
  • A kind of preparation method of amino polyethylene glycol propionic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0076] Embodiment 1: the preparation of aminotriethylene glycol propionic acid

[0077] In a 20-liter glass reactor, 500 g of ethanolamine, 10 L of acetonitrile and 2200 g of potassium carbonate were successively added. The reaction solution was cooled to -10°C, and 2800 g of benzyl bromide was added dropwise to the reaction solution for 5 hours. After the addition was complete, the temperature of the reaction solution was raised to 50° C., and the reaction was continued for 3.0 h. HPLC detection showed that the raw materials had reacted completely. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 1920 g of light yellow solid.

[0078] Add 1920g of light yellow oily liquid obtained in the previous step and 10L of dichloromethane into a 20-liter glass reactor, cool the reaction solution to -10°C, and add 1060g of thionyl chloride dropwise to the reaction solution for 3 hours. After the addition was ...

Embodiment 2

[0085] Embodiment 2: the preparation of aminotetraethylene glycol propionic acid

[0086] In a 20-liter glass reactor, 440 g of ethanolamine, 8.0 L of acetonitrile and 2190 g of sodium carbonate were sequentially added. The reaction solution was cooled to 0°C, and 2492 g of benzyl bromide was added dropwise to the reaction solution for 5 hours. After the addition was complete, the temperature of the reaction solution was raised to 50° C., and the reaction was continued for 3.0 h. HPLC detection showed that the raw materials had reacted completely. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 1700 g of a light yellow solid.

[0087] Add 1700g of the light yellow oily liquid and 8.0L of dichloromethane obtained in the previous step into a 20-liter glass reactor, cool the reaction solution to 0°C, and add 966g of thionyl chloride dropwise to the reaction solution for 2 hours. After the addition wa...

Embodiment 3

[0095] Embodiment 3: the preparation of amino pentaethylene glycol propionic acid

[0096] 300 g of ethanolamine, 6.0 L of acetonitrile and 1200 g of potassium carbonate were successively added into a 20-liter glass reactor. The reaction solution was cooled to 0°C, and 1850 g of benzyl bromide was added dropwise to the reaction solution for 5.5 hours. After the addition was complete, the temperature of the reaction solution was raised to 50° C., and the reaction was continued for 3.0 h. HPLC detection showed that the raw materials had reacted completely. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 1180 g of a light yellow solid.

[0097]Add 1180g of light yellow oily liquid obtained in the previous step and 6.0L of dichloromethane into a 20-liter glass reactor, cool the reaction solution to 0°C, and add 660g of thionyl chloride dropwise to the reaction solution for 2.5 hours. . After the addi...

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Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of amino polyethylene glycol propionic acid. The preparation method comprises the steps that catalytic hydrogenation is carried out on dibenzyl amino polyethylene glycol tert-butyl propionate shown in formula I-2 to obtain amino polyethylene glycol tert-butyl propionate shown in formula I-3; (2) the amino polyethylene glycol tert-butyl propionate shown in formula I-3 is hydrolyzed under the acidic condition to obtain amino polyethylene glycol propionic acid shown in formula I. The preparation methodof the amino polyethylene glycol propionic acid has the advantages that the defects in the prior art that the yield is low, the dangerousness is high, and the enlargement of production is difficult are overcome, the reaction conditions are mild, the operation is simple, an intermediate does not to be purified, the next reaction can be directly carried out, the whole yield reaches up to 87-92%, thepurity of end products reaches up to 97-99.5%, and a safe and efficient synthetic route is provided for the preparation of amino polyethylene glycol propionic acid.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of aminopolyethylene glycol propionic acid. Background technique [0002] Polyethylene glycol (PEG) is formed by ring-opening polymerization of ethylene oxide, and the ratio of oxygen to carbon in its molecular formula is as high as 1:2. This unique structure endows it with excellent water solubility and biocompatibility. Coupling polyethylene glycol to the surface of polypeptide or protein drugs can increase the water solubility of the drug, prolong the half-life of the drug, reduce the immunogenicity of the drug, and polyethylene glycol has low toxicity, can be excreted by the kidneys, and will not accumulate in the body. In order to facilitate the coupling of polyethylene glycol and drugs, polyethylene glycol needs to be modified in advance. Aminopolyethylene glycol propionic acid is such a modified polyethylene glycol reagent, which has amino and carbox...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/08C07C213/06C07C213/08C07C215/08C07C209/74C07C211/15
CPCC07C209/74C07C213/06C07C213/08C07C215/08C07C211/15C07C217/08
Inventor 沈军伟章方良张建齐罗福林
Owner JIANGSU GENSCRIPT BIOTECH CO LTD