Method for preparing solid-phase synthesis carrier based on chloroacetylated crosslinked polystyrene resin

Abstract

The invention discloses a method for preparing a solid-phase synthesis carrier based on chloroacetylated crosslinked polystyrene resin (PS-COCH2-Cl). The method comprises: swelling PS-COCH2-Cl in a solvent for 2-3 h, respectively adding 2-hydroxybenzyl alcohol, an inorganic base and a phase-transfer catalyst, and reacting at 40-120 DEG C for 1-48 h, so as to obtain the solid-phase synthetic carrier. According to the method, chloroacetylated polystyrene resin (PS-COCH2-Cl) replaces conventional chloromethylated polystyrene resin, so that carcinogenic substances are prevented from being used in the resin preparation process; also, chloroacetyl can be exclusively reacted with phenolic hydroxy, and a side reaction between hydroxymethyl and chloroacetyl can be avoided; the phase-transfer catalyst helps to enable the reaction to be performed mildlyin the presence of inorganic base; and 2-hydroxybenzyl alcohol replaces conventionally used p-hydroxybenzyl alcohol, so that on the one hand, the price is relatively preponderant, and on the other hand, conditions required by reactions of removal of polypeptide micromolecules and the carrier are relatively mild.

Description

technical field [0001] The invention relates to a method for solid-phase synthesis of a carrier based on chloroacetylated cross-linked polystyrene resin, which belongs to the technical field of functional polymer materials. Background technique [0002] The synthesis of small molecule peptides is a very active field in protein and peptide chemistry, and the basic synthesis methods can be divided into two categories: liquid phase synthesis and solid phase synthesis. Introduced by Robert Bruce Merrifield in 1963, the solid-phase method, now known as solid-phase peptide synthesis (SPPS), was a major breakthrough in peptide chemistry. Compared with the traditional liquid-phase process, the solid-phase method has many advantages, such as shortened production cycle, and generally has higher yield and purity. It plays an important role in the progress of many peptide drug research. The overall efficiency of solid phase methods has generally increased with the advent of new conden...

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Problems solved by technology

However, such resins have the following disadvantages at present: 1) chloromethyl ether, a strong carcinogen, is used as a raw material in the synthetic raw material chloromethylated polystyrene reaction (Roland LD, et al, Chemistry. & Industry, 1993, 4 (1): 10); 2) The chloromethylation reaction will be accompanied by multiple substitutions of chloromethyl groups and secondary crosslinking, which will affect the performance of the resin (Barrett J, et al, US 3812061, 1997); 3) In the follow-up reaction with p-hydroxybenzyl alcohol, the traditional synthetic method will use sodium methoxide. Due to the strong nucleophilic ability of methoxy, it is easy to replace active chlorine and cause side reactions (Lu GS, et al. J. Org. Chem. 1981, 46, 3433-3436), which in turn affects the loading rate of the solid phase carrier in the subsequent solid phase synthesis reaction