CN-121990981-A - Soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof

Abstract

The invention belongs to the technical field of polypeptide liquid phase synthesis carriers, and discloses a soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof. The structural formula of the soluble liquid phase carrier for polypeptide liquid phase synthesis is The soluble liquid phase carrier provided by the invention not only has excellent performance in the aspects of improving the operation efficiency, being convenient for monitoring the reaction process and the like, but also has the advantages of economy and sustainable use, can obviously improve the efficiency and controllability of the liquid phase synthesis process of the polypeptide, and has extremely strong practicability when being applied to the liquid phase synthesis of the polypeptide.

Inventors

• CHEN XING
• HUANG XIHONG

Assignees

• 成都赛科洛生物科技有限公司

Dates

Publication Date

20260508

Application Date

20260410

Claims (10)

1. 1. A soluble liquid phase carrier for polypeptide liquid phase synthesis has a structure shown in a formula (I): (I) Wherein: the group R is selected from H, methoxy, halogen, alkyl, aldehyde group and nitro, and the number of the groups R is 1-3; The number of the groups Linker-Tag is 1-3; Linker is selected from bivalent groups formed by removing hydrogen atoms on hydroxyl groups and amino groups of the compound shown in the following structural formula: ; tag is selected from monovalent groups formed by removing a group X from a compound represented by the following structural formula: ; ; Wherein the group X is selected from F, cl, br, I, trifluoromethanesulfonic acid group, p-toluenesulfonic acid group and p-toluenesulfonic acid group.
2. 2. The soluble liquid phase support of claim 1, wherein the soluble liquid phase support is selected from the group consisting of the following structural formulas: ; ; 。
3. 3. The soluble liquid phase carrier of claim 2, wherein formula A is selected from the group consisting of: ; ; 。
4. 4. the soluble liquid phase carrier of claim 2, wherein formula B is selected from the group consisting of: ; ; 。
5. 5. the soluble liquid phase carrier of claim 2, wherein formula C is selected from the group consisting of: 。
6. 6. The soluble liquid phase carrier of claim 2, wherein formula D is selected from the group consisting of: 。
7. 7. the soluble liquid phase carrier of claim 2, wherein formula E is selected from the group consisting of: 。
8. 8. the soluble liquid phase carrier of claim 2, wherein: The structural formula F is specifically as follows: ; The structural formula G is specifically as follows: 。
9. 9. Use of a soluble liquid phase carrier according to any one of claims 1 to 8 in the liquid phase synthesis of a polypeptide.
10. 10. The method according to claim 9, wherein the polypeptide is a teriparatide fragment, and the sequence is Fmoc-Ser (tBu) -Val-Ser (tBu) -Glu (trt) -Ile-Gln (trt) -Leu-Met-His (trt) -Asn (trt) -Leu-OH.

Description

Soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof Technical Field The invention relates to the technical field of polypeptide liquid phase synthesis carriers, in particular to a soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof. Background Chemical synthesis of a polypeptide refers to a process in which amino acids are dehydrated and condensed to form peptide bonds by chemical means, and the peptide bonds are gradually formed by extension. The chemical synthesis of polypeptide mainly adopts solid phase synthesis method and liquid phase synthesis method. The main steps of the solid phase synthesis method are that firstly protecting the amino group of amino acid with protective agent such as Fmoc, boc, etc., then combining the carboxyl end of the first amino acid with resin, removing the protective agent of the amino end, then connecting the second amino acid, repeating the steps to condense the required amino acid sequence according to a certain sequence, finally cutting the polypeptide from the resin under the acid condition, and purifying to obtain the required polypeptide. The solid phase synthesis method has certain advantages in speed, has a pseudo-dilution effect, can effectively reduce side reactions and is easy to control racemization of amino acids, so that the solid phase synthesis method is a current general polypeptide synthesis method. However, solid phase synthesis has certain limitations due to the high price of the solid phase synthesis carrier and the large amount of reagents used for washing during the synthesis process. The conventional liquid phase synthesis method is characterized in that amino acid is coupled in a certain solvent to obtain corresponding polypeptide, the corresponding polypeptide is generally in homogeneous phase reaction, the reactivity is good, the used reagent is generally only required to be equivalent or slightly excessive, and the intermediate can be further purified to the purity required by the process through means of washing, crystallization, chromatography or preparative chromatography. The conventional liquid phase synthesis method has the advantages of low cost, high flexibility and high workload, and has the defect of difficult synthesis of long peptide chain amino acid. In recent years, in order to improve the problem of high price of solid-phase synthesis carriers, a method of liquid-phase synthesis of polypeptides by combining a solid-phase synthesis method and a liquid-phase synthesis carrier having a specific structure has been studied, wherein a reaction is carried out by connecting a reactant to a soluble liquid-phase synthesis carrier, the reaction is carried out in a homogeneous system, and after the completion of the reaction, a carrier-product complex is precipitated by changing the conditions such as polarity of a solvent and temperature, thereby realizing separation of a product. The method can greatly improve the purity of the liquid phase synthesized polypeptide or the intermediate thereof, effectively reduce the racemization problem of amino acid, reduce the production cost of polypeptide medicaments and improve the production efficiency. However, the liquid phase synthesis method of polypeptide based on liquid phase synthesis carrier has two defects at present. On one hand, the solubility requirement on the liquid phase synthesis carrier is higher, if the carrier has poor solubility, incomplete reaction and polypeptide aggregation and precipitation are caused, the synthesis length is limited, and meanwhile, the precipitation-dissolution purification process is destroyed, so that impurity accumulation is caused, and the final yield and purity are greatly reduced. On the other hand, as the peptide chain increases, the crystal precipitation state becomes worse, resulting in difficulty in washing and prolonged washing time, and there are cases where washing is insufficient, which is disadvantageous for production of high quality polypeptide. For example, since the liquid carrier AJIPHASE of Weisu Co., ltd. Is mainly composed of benzene ring and fatty chain, the synthesis of long peptide chain can be performed, and the cost is low and the flexibility is high. However, AJIPHASE has the defects of poor solubility in conventional reagents, need to use chloroform which is a solvent with high toxicity and is regulated as a liquid phase and is sensitive to partial polarity or poor in suitability of a very long peptide chain, is in paste form after the peptide chain is separated out, is difficult to suction filter, needs long washing time, and is easy to cause insufficient washing, so that the impurity content of the polypeptide is high and the purity is low. Disclosure of Invention The invention aims to solve the technical problems of providing a soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof, which have the advantages of go