Goserelin acetate solid-phase synthesis method

Abstract

The invention relates to a goserelin acetate solid-phase synthesis method, which comprises the following steps: HBTU/DIPEA is employed as a condensation system, Fmoc-Ser-OH, Fmoc-Trp-OH are successively coupled; a whole-protection lysate with corresponding voluminal amount according to 10 times of resin weight is added, a carrier 2-CTC Resin in an intermediate is removed, all side chain protective groups are reserved; the whole-protection lysate is adjusted to slight alkaline by using DIPEA(N,N-diisopropylethylaine), semicarbazide hydrochloride and PyBop(1H-benzotriazole-1-oxygen tripyrrole alkyl hexafluorophosphate) (used for a coupling agent of peptide) are added in the whole-protection lysate for reaction coupling, a goserelin peptide solution with the side chain protective group is obtained; the lysate with 20% of TFA/DCM is added in a freezing ether for settling to obtain the white solid crude peptide; the white solid crude peptide is dried under vacuum for solving by methyl alcohol, ammonium formate and Pa/c are added for a hydrogenation reaction to remove the side chain protective group in a peptide sequence. According to the invention, side reaction phenomena can be avoided, target peptide purity is increased, yield is high, operation is convenient and feasible, the intermediate can be tracked and controlled, and the whole process is benefit for enlarged 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 acetate. Background technique [0002] Goserelin, its cultural name: pyroglutamyl-L-histidyl-L-tryptophanyl-L-tyrosyl-D-seryl-L-leucyl-arginyl-proline Acyl-aminouria; English name: Goserelin, molecular formula: C59H84N18O14, molecular weight: 1269.4105; applicable symptoms: 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 medicatio...

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, 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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