Preparation method of high-purity polyethylene glycol aldehyde derivative

Abstract

The invention discloses a preparation method of a high-purity polyethylene glycol aldehyde derivative. The preparation method comprises the steps that 1, PEG terminal hydroxyl groups are converted into groups with higher activity to obtain a PEG active intermediate, and the PEG active intermediate and a small molecule compound of an alpha-hydroxy acid or beta amino alcohol or alpha-aminoketones structure react to obtain a polyethylene glycol intermediate; 2, the polyethylene glycol intermediate is separated and purified by ion exchange resin; 3, the polyethylene glycol intermediate is oxidized by an oxidizing agent to obtain the polyethylene glycol aldehyde derivative. According to the preparation method, the polyethylene glycol intermediate with the high purity is obtained through separation and purification of the ion exchange resin, then quantitative oxidation is carried out through the oxidizing agent, and therefore the high-purity polyethylene glycol aldehyde derivative is obtained. The high purity means that the content of the polyethylene glycol aldehyde derivative is more than 98%. The preparation method is an economical method suitable for commercialized production.

Description

technical field [0001] The invention relates to a preparation method of high-purity polyethylene glycol aldehyde derivatives. Background technique [0002] Polyethylene glycol (PEG) is an extremely versatile synthetic polymer compound, which is mainly used in many fields such as biomedicine, chemical industry, food, and material science. PEG is easily soluble in water and organic solvents, and has good physical and chemical properties and biocompatibility. In biomedicine, PEG is widely used as an excipient in pharmaceutical preparations, sustained-release and targeting studies because of its amphiphilicity, good safety, biocompatibility, inactivity, and no toxic or side effects. It can also be covalently linked to proteins or polypeptides to improve the biochemical and pharmacokinetic properties of proteins and polypeptide drugs, and even for the modification of small molecule drugs. A large number of studies have shown that the antigenicity of PEG-modified polypeptides an...

AI Technical Summary

Problems solved by technology

The oxidation method is obtained by directly oxidizing the terminal hydroxyl group of the PEG chain, for example, adding oxygen to the mixture of PEG and catalyst to oxidize the terminal hydroxyl group of the PEG chain into an aldehyde group, or using MnO 2 etc. as an oxidant to directly oxidize terminal hydroxyl groups, but in most cases, these oxidation conditions easily lead to the decomposition of PEG chains, and the conversion rate of PEG chain end groups is not high, most of which are below 80%.

The acetal method is obtained by introducing an acetal group at the end of the PEG chain followed by hydrolysis, but the reactant raw materials used in this method are relatively expensive and not suitable for commercialization, and because the terminal functional groups of the PEG chain are converted without intermediate purification steps , therefore, the purity of the obtained product is still limited

Since the prepared PEG aldehyde is impure, it will contain many by-products, which brings risks to the modification of drugs and affects the modification efficiency of PEG on protein and polypeptide drugs.

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