Method for preparing thymopentin

Abstract

The invention relates to the preparation of polypeptide medicines, in particular to a method for preparing an anti-tumor adjuvant medicine, namely thymopentin. The method for preparing the thymopentin comprises the following steps of: mixing an amino acid resin, namely polyethylene glycol (PEG)-wang resin-Tyr(tbu)-OH and a super absorbent resin; dissolving Fmoc-Val-OH into a dichloromethane (DCM) / dimethylformamide (DMF) solution, and adding the obtained solution into the mixed resin together with a 1-hydroxybenzotriazole (HOBt) / DMF / diisopropylcarbodiimide (DIC) mixed solution; sequentially washing by using DMF, ethanol and DCM to finish the connection of the Fmoc-Val-OH; and sequentially connecting Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Boc)-OH and Fmoc-Arg-OH by the same method, performing pyrolysis by using a pyrolysis reagent in which the ratio of trifluoroacetic acid (TFA) to ethylenediamine tartrate (EDT) to water is 95:3:2 after connection, filtering the resin, adding a filtrate into absolute ether, sucking supernatant out after settlement, adding purified water of which the volume is the same as that of a precipitate into the precipitate, shaking, standing, demixing, extracting an aqueous layer by using the absolute ether, washing, concentrating, and freeze-drying a concentrated solution to obtain the thymopentin.

Description

technical field [0001] The invention relates to the preparation of polypeptide drugs, in particular to a preparation method of thymopentin, an anti-tumor auxiliary drug. Background technique [0002] Thymopentin (Thymopentin), also known as TP-5, Thymopentin, its structural formula and polypeptide sequence are: [0003] [0004] Molecular formula: C 30 h 49 N 9 o 9 , molecular weight: 679.77. [0005] The existing thymopentin preparation is thymopentin for injection, which is mainly used clinically for the treatment of hepatitis B and adjuvant anti-tumor drugs, and is a two-way immunomodulatory drug. [0006] There are many known preparation methods for preparing thymopentin by solid-phase synthesis, but most of them have the problems of long synthesis cycle, low yield and poor purity of crude product in industrialization. [0007] The process of using Boc-protected amino acids as starting materials in early industrialization has been gradually eliminated, because T...

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Problems solved by technology

[0015] Chinese patent CN200410002607 "Synthesis of Thymopentin by Mixed Anhydride Method" introduces palladium carbon in the reaction process, which is rarely used in the current industrial production of polypeptides, mainly because palladium carbon is expensive and palladium carbon is easy to spontaneously ignite in organic solvents. to safety hazard

This method is a liquid-phase synthesis method, and each step needs to be refined and purified. While the operation is cumbersome, the yield is bound to be greatly reduced after multiple purifications, and the industrialization prospect is not optimistic.

[0018] In the above-mentioned patents and literature reports, it is not difficult to find that the influence of resin swelling degree on the condensation reaction and the dissolution of other coupled amino acids were not considered in the whole process of solid-phase synthesis of thymopentin using the Fmoc protection strategy. The characteristics and the control of the moisture generated by the reaction, in the whole reaction process, mostly use the 2-5 times excess of the condensed protected amino acid as a means to solve the condensation efficiency

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