Preparation method of buserelin or goserelin

Abstract

The invention relates to a preparation method of buserelin or goserelin. The method comprises the following steps: 1) preparing Fmoc-Pro-resin by using 2-CTC resin as a carrier; 2) preparing fully-protected 9 peptide resin by a solid-phase synthesis technology; 3) pyrolyzing the fully-protected 9 peptide resin to obtain a fully-protected 9 peptide; 4) reacting the fully-protected 9 peptide with ethylamine hydrochloride under the action of a coupling agent to obtain fully-protected buserelin, or reacting the fully-protected 9 peptide with semicarbazide hydrochloride under the action of the coupling agent to obtain fully-protected goserelin; 5) carrying out a palladium-carbon catalyzed hydrogenolysis reaction on the fully-protected buserelin or the fully-protected goserelin in a solvent Z, and filtering out the palladium-carbon after the reaction is finished in order to obtain a buserelin solution or a goserelin solution; and 6) purifying and freeze-drying the buserelin solution or the goserelin solution to obtain the buserelin or goserelin, wherein the solvent Z in step 5) is a methanol solution containing 5% of pyridine hydrochloride or an aqueous solution containing 85-95% of acetic acid.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of buserelin or goserelin. Background technique [0002] Both Buserelin and Goserelin belong to gonadotropin-releasing hormone (GnRH) analogues, and their structures are represented by amino acid abbreviations: Pyr-His-Trp-Ser-Tyr-D-Ser( tBu)-Leu-Arg-Pro-R, when R=NHEt in buserelin, R=Azgly-NH in goserelin 2 , the structural formula is as follows: [0003] [0004] Currently, the synthesis methods of buserelin and goserelin include solid-phase synthesis and liquid-phase synthesis. Liquid phase synthesis methods are mostly found in early literature, such as WO97 / 48726 and EP1008656. However, the liquid-phase synthesis operation is complicated, and each synthesis step must be purified, which is not conducive to industrial production and has low application value. Since the D-Ser side chain tBu in buserelin and goserelin is not compatible with the Fmo...

AI Technical Summary

Problems solved by technology

We found that the Trt protecting group in His(Trt) is difficult to remove by conventional hydrogen transfer reaction or catalytic hydrogenolysis or the reaction is very slow. The content of large impurities

Therefore, in actual production, the dichloromethane solution of TFA is currently used for removal, but this method will inevitably have two problems: (1) the tert-butyl ether of D-Ser that needs to be retained in the molecule is also sensitive to acid group, so there will be a side reaction to remove the tert-butyl ether; (2) after the reaction is completed, when the reaction solvent is evaporated under reduced pressure, the composition ratio of TFA in the reaction system will continue to change, and the distillation time will also be affected by the state of the equipment, etc. It is difficult to control accurately due to the influence of factors, and these will affect the side reaction of removing tert-butyl ether, resulting in unstable production process and bringing uncertainty to actual production

[0007] In addition, in actual experiments, we found that the solubility of fully protected buserelin and goserelin in methanol and ethanol is very small, because the solvents commonly used in conventional hydrogen transfer reactions and hydrogenolysis reactions are methanol and ethanol, so Removal of Bzl and NO by conventional methods 2 Due to the solubility problem of the protecting group, the reaction is very slow or the amount of catalyst is too large, which brings many safety hazards

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