Method for synthesizing Degarelix

Abstract

The invention relates to the field of medicine synthesizing and discloses a method for synthesizing Degarelix. The method is characterized in that the synthesizing of the whole Degarelix is separated into two parts from the fifth amino acid position to the sixth amino acid position, appropriate protecting groups are used for parts of protecting amino acid, and the whole synthesizing process is completed by using specific acidulate agents. The method has the advantages that an appropriate synthesizing scheme is selected, the suitable protecting groups and acidulate agents are selected, the whole synthesizing process is optimized, the purity of the Degarelix is increased evidently, high total yield is achieved, and generation of toxic hydantoin degradation products is avoided.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing degarelix. Background technique [0002] Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug developed by Danish Ferring Pharmaceutical Co., Ltd., which reversibly inhibits the pituitary GnRH receptor to reduce the release of gonadotropin and then inhibit the release of testosterone. This product slows the growth and progression of prostate cancer by inhibiting testosterone, which is essential for the continued growth of prostate cancer. Hormone therapy for prostate cancer to lower testosterone levels initially caused a spike in testosterone levels, and this initial stimulation of the hormone receptor temporarily boosted tumor growth rather than inhibiting it, whereas degarelix did not. The U.S. FDA approved Degarelix for marketing in December 2008. It is mainly aimed at patients with advanced prostate cancer and delays...

AI Technical Summary

Problems solved by technology

[0008] Chinese patent CN201310336446.7 adopts the Fmoc synthesis method. The preparation scale reported by this method is also very small. In order to avoid the generation of toxic degradation products of the rearrangement product hydantoin of Aph(Hor) under alkaline conditions, a The solid-phase fragment condensation method and the unique protected amino acids Aph(Mmt / Dmt) and Aph(Cbm) are relatively complicated to operate, and the protected amino acids and fragments used are expensive and the production cost is high; Chinese patent CN201210460195.9 adopts Fmoc solid-phase synthesis method, the preparation scale reported by this method is also very small, in order to avoid the generation of Aph (Hor) rearrangement product hydantoin under alkaline conditions, the protective group Trt that can be deprotected has been adopted to Aph, but it is in The use of TFA / DCM in the deprotection process will cause the Boc part of the protected amino acid Lys (iPr, Boc) to fall off, so that the exposed amino group of Lys (iPr) can be combined with the subsequent L-4,5-, dihydro-orhey The acid reaction produces new impurities, and its operation is also relatively complicated. The protected amino acid used is expensive and the production cost is high; in addition, the above two patents still have the problem of low yield of degarelix, which is about 40%. These are related to its overall synthesis process

[0009] Chinese patent CN201410427405.4 adopts Fmoc solid-phase synthesis method, which has the simplest operation route and higher yield than the aforementioned two Chinese patents, but it cannot avoid the rearrangement of Aph(Hor) in the structure under alkaline conditions. The production of hydantoin degradation products, and the protected amino acids of Aph (Cbm) and Aph (Hor) used at the same time are also very expensive, and the process cost is relatively high

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