Liquid-phase synthesis method of snake venom-like tripeptide

Abstract

The invention discloses a liquid-phase synthesis method of snake venom-like tripeptide. The method comprises the following steps: using raw materials Fmoc-Da (Boc)-OH, benzylamine, Boc-beta-Ala-OH andH-Pro-OMe. HCl / H-Pro-OBzl. HCl as raw materials and DIC / HOBt, DIC / HOAt, EDC / HOBT, HATU, HBTU and the like as reagents, synthesizing polypeptide H-beta-Ala-Pro-Dab(Boc)-NHBzl, then cutting off a protective group Boc under an acidic condition and purifying to obtain the product. The product H-beta-Ala-Pro-Dab(Boc)-NHBzl is directly obtained by using a solid-phase synthesis method, the stability problem of CTC resin is solved in the product, the racemization problem of Dab is avoided by adopting a method of connecting Fmoc-Db (Boc)-OH and benzylamine, and the synthesis method is short in processroute, very short in production period, suitable for large-scale production, good in method stability and suitable for large-scale production.

Description

technical field [0001] The present invention relates to the preparation method of polypeptide. More specifically, the present invention relates to the preparation method of H-β-Ala-Pro-Dab-NHBzl. Background technique [0002] H-β-Ala-Pro-Dab-NHBzl is a small molecular peptide that mimics the activity of snake venom Waglerin I. Clinical trials have shown that this peptide can reduce wrinkles by inhibiting muscle contraction, and has excellent smoothing and rapid wrinkle removal properties , H-β-Ala-Pro-Dab-NH-Bzl acts on the postsynaptic membrane and is a reversible antagonist of the muscle nicotinic acetylcholine receptor (mmAChR), looking for a suitable synthetic method for the small molecular polypeptide Industrialization is of great significance. [0003] Commonly used chemical synthesis methods for peptide synthesis include liquid-phase synthesis and solid-phase synthesis. For small molecule peptides, generally less than 10 amino acids, the common method is to use liqu...

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Problems solved by technology

In addition, in the connection reaction between Boc-β-Ala-Pro-Dab(Boc)-OH and benzylamine, because the main chain amino acid of Dab(Boc) is not an oxycarbonyl protecting group, it is very easy to produce Dab in the condensation reaction. The racemization has a great influence on the product quality

[0005] Publication No. CN107857797A, the technical route mentioned in the invention patent whose patent name is a liquid-phase fragment synthesis method of snake venom tripeptide, firstly Fmoc-Pro-OH is prepared into Fmoc-Pro-OSu and H-Dab(Boc )-OH reaction forms the reaction process of Fmoc-Pro-Dab(Boc)-OH, the reaction will be more difficult due to the larger steric hindrance of Pro amino acid, and the yield will be lower; in addition, in Fmoc-Pro-Dab( In the connection reaction between Boc)-OH and benzylamine, because the Dab(Boc) main chain amino acid is not an oxycarbonyl protecting group, it is very easy to produce Dab racemization in the condensation reaction, which has a great impact on product quality

[0006] Publication No. CN103570804A, the patent name is a liquid-phase fragment synthesis method of snake venom tripeptides. In the technical route mentioned in the invention patent, a solid-liquid combination method is used to obtain snake venom tripeptides. In this process route, CTC resin is used, and CTC resin itself has very stability problems, and process control is difficult

In the connection reaction between Boc-β-Ala-Pro-Dab(Boc)-OH and benzylamine, because the main chain amino acid of Dab(Boc) is not an oxycarbonyl protecting group, it is very easy to produce the elimination of Dab in the condensation reaction. Rotation has a great influence on product quality

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