Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 1.

The present invention relates to the field of medicinal synthesis, and discloses a method for synthesizing degarelix. The method of the present invention as a whole divides the synthesis of degarelix into two parts from amino acids at positions 5 and 6, employs proper protective groups in part of the protected amino acids therein, and finally uses in association with a specific acidolysis agent to complete the whole synthesis process. In the present invention, a proper synthesizing scheme is selected, and adaptive protective group and acidolysis agent are selected, so that the overall synthesis process is optimized, the purity of degarelix is significantly improved with a higer total yield, and the production of the toxic hydantoin degradation product is avoided.

Method For Synthesizing Degarelix

The invention discloses synthesis of degarelix by a solid phase segment method, wherein Fmoc-amino acid is connected with resin so that Fmoc-amino acid-resin can be obtained; a solid phase synthesis method is adopted, and the steps of orderly connecting amino acid from the end C to the end N and removing the Fmoc group are carried out, so that Fmoc protected polypeptide resin can be obtained; the method comprises the following steps of: (1) forming polypeptide resin as shown in formula III and polypeptide resin as shown in formula IV, respectively; (2) mixing the polypeptide resin as shown in formula III with 1-5% of trifluoroacetic acid (TFA), connecting L-4,5-dihydroorotate to the side chain amino of the polypeptide resin after the protecting group of the sixth amino acid residue at the end C is removed, and then removing the Fmoc group to obtain polypeptide resin as shown in formula V; removing the Fmoc group of the polypeptide resin as shown in formula IV and acetylating the polypeptide resin, thereby obtaining polypeptide resin as shown in formula VI, and then cutting to obtain segments as shown in formula VII; (3) coupling the polypeptide resin as shown in the formula V with the segments as shown in the formula VII, thereby obtaining the polypeptide resin as shown in formula II; (4) separating polypeptide on the polypeptide resin as shown in the formula II from the resin, thereby obtaining degarelix as shown in formula I.

Synthesis of degarelix by solid phase segment method

The invention discloses a safe, high-efficiency degarelix synthesis method, particularly a preparation method for a degarelix. With amino resin as an initial resin carrier, the method disclosed by the invention sequentially connects corresponding Fmoc-amino acids in a degarelix sequence by solid-phase synthesis, wherein Ac-D-2Nal-OH is adopted as the last amino acid, and by condensation reaction and deprotection reaction, fully protected degarelix peptide resin is obtained; acidolysis segmentation and ether sedimentation are then carried out, so that crude degarelix peptide is obtained; by chromatographic purification, acetic acid salinization and freeze drying, the acetic acid degarelix is obtained. The preparation method chooses Oxyma as safe, high-efficiency coupling reagent in order to increase the safety of the process and reduce the byproducts of the process. The process can adopt not only solid-phase synthesis but also liquid-phase synthesis, the byproducts of the process are little, and separation and purification are easy. The purity of the obtained final acetic acid degarelix product is up to 99 percent, the yield is up to 61 percent, and the final acetic acid degarelix product has considerable economically applicable value and a broad application prospect.

Preparation method for degarelix

The invention relates to a method for preparing Degarelix acetate. The method comprises the following steps of orderly coupling ten amino acids such as Fmoc-D-Ala-OH, Fmoc-Pro-OH, Fmoc-Ilys(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-4Aph(Dde)-OH, Fmoc-4Aph(Teoc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-D-3Pal-OH, Fmoc-D-Phe(4Cl)-OH and Fmoc-D-2Nal-OH to RinkAmideMBHA resin, removing a protecting group Fmoc, carrying out acetic anhydride termination, then removing Dde of the amino group of the 6-site D-phenylalanine side chain by a DMF mixed solution containing 2% of hydrazine hydrate, introducing Cbm by a DMF solution of trimethylsilyl isocyanate, removing Teoc of the amino group of the 5-site phenylalanine side chain by a tetrabutylammonium fluoride-DMF mixed solution, introducing L-Hor on the amino group by a coupling reaction, and carrying out cracking, purification and freeze-drying to obtain the Degarelix acetate. The method utilizes a stepwise, orthogonal and high-specific protecting group synthesis strategy to prepare Degarelix acetate, realizes direct synthesis and modification of an effective member on the carrier, effectively improves a yield and reduces a cost.

Method for preparing Degarelix acetate

The invention discloses a method for synthesizing degarelix, wherein an amino resin protected with Fmoc is used as a raw material; according to a solid-phase synthesis method, DIC/HOBt (N,N'-diisopropylcarbodiimide/1-hydroxybenzotrizole) is used as a coupling agent for transpeptidase reaction; 4-serine uses tert-butyl dimethyl to replace tertiary butyl for protection protecting hydroxyl; a hydroorotic acid fragment connected with 4-amino of 5-phenylalanine benzene ring is protected with triphenylmethyl at first, and then introduced, so that the rearrangement side reaction is prevented; and since D-4Aph (Cbm) is used for replacing D-4Aph (Cbm-tBu), a t-Bu removal difficulty is prevented and the occurrence of the side reaction is reduced. A synthesis technology of the method for synthesizing degarelix is simple in steps, easy to control, small in environment pollution and high in yield, thereby being applicable for industrial production.

Method for synthesizing degarelix

The invention discloses a manual synthetic method for 1,4,5,6-tetrahydronaphthalene-2-methyl-4-pyrimidine carboxylic acid. The method comprises the following steps of: synthesizing 1,4,5,6-tetrahydronaphthalene-2-methyl-4-pyrimidine carboxylic acid by using small molecule alcohols as solvents and L-2,4-biaminobutyric acid bihydrochloride and trimethyl orthoacetate as raw materials. The synthetic process is simple in steps, short in reaction time, easy to control, low in environment pollution, high in yield and suitable for industrial production.

Manual synthetic method for tetrahydropyrimidine hydrochloride

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Method for synthesizing degarelix

Manual synthetic method for tetrahydropyrimidine hydrochloride