Solid-phase synthesis of goserelin

Abstract

The invention discloses a solid-phase synthesis method of goserelin, comprising: adopting HBTU / DIPEA as a condensation system, sequentially coupling Fmoc-Ser-OH, Fmoc-Trp-OH; Double the corresponding volume to remove the carrier 2-CTC Resin in the intermediate product, but keep all the side chain protecting groups; adjust the fully protected lysate to be slightly alkaline with DIPEA (N,N-diisopropylethylamine) Add semicarbazide hydrochloride and PyBop (1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate [coupling agent for peptides) to the fully protected lysate for reaction coupling to obtain the retained side Goserelin peptide solution with chain protecting group; add 20% TFA / DCM lysate into frozen diethyl ether to settle to obtain white solid crude peptide; vacuum dry the white solid crude peptide and dissolve it in methanol, add ammonium formate and Pa / c carry out hydrogenation reaction to remove the side chain protecting group in the peptide sequence. The invention avoids many side reactions, improves the purity of the target peptide, and has a relatively high yield. The operation is convenient and feasible, and the intermediate can be tracked and controlled, and the whole process is beneficial to scale-up production.

Description

technical field [0001] The invention relates to the field of chemical synthesis of polypeptide drugs, in particular to a solid-phase synthesis method of goserelin. Background technique [0002] Goserelin, its cultural name: pyroglutamyl-L-histidyl-L-tryptophanyl-seryl-L-tyrosyl-D-seryl-L-leucyl-arginine Acyl-prolyl-semicarbazide; English name: Goserelin, molecular formula: C59H84N18O14, molecular weight: 1269.4105; applicable diseases: suitable for prostate cancer and premenopausal and menopausal breast cancer that can be treated with hormones. endometriosis; [0003] [0004] This drug is a synthetic analog of luteinizing hormone-releasing hormone. Long-term use can inhibit the secretion of luteinizing hormone in the pituitary gland, thereby causing a decline in male serum testosterone and female serum estradiol. The effect is reversible. For male patients, the testosterone concentration can be reduced to the post-castration level about 21 days after the first medicat...

AI Technical Summary

Problems solved by technology

First of all, it will cause many side reactions in the synthesis process, resulting in low purity of the target peptide and difficult purification. In addition, in the synthesis process, Rink Amide MBHA Reain is used to react with N,N'-carbonyldiimidazole to generate intermediate products and then Reaction with Fmoc-NH-NH2 to obtain Fmoc-NH-NH-CO-NH-Resin cannot be traced throughout the entire process, and the degree of coupling reaction and coupling effect cannot be determined, and the scale-up production of the entire process is difficult to achieve

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