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The synthetic method of degarelix acetate
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A technology for the synthesis of degarelix acetate, which is applied in the field of organic synthesis and can solve the problems of low yield, high cost, and many side reactions
Active Publication Date: 2021-03-16
天津凯诺医药科技发展有限公司
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[0010] The main purpose of the present invention is to provide a synthetic method of degarelix acetate, so as to solve the problems of many side reactions, low yield and high cost in the preparation of degarelix acetate by solid phase synthesis in the prior art
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[0030] As described in the background technology section of the present invention, the preparation of degarelix by solid-phase synthesis method in the prior art often has the problems of many side reactions, low yield and high cost. In order to solve this problem, the present invention provides a synthetic method of degarelix acetate, which includes: S1, using Rink Amide MBHA resin as a carrier for solid-phase synthesis, which is sequentially mixed with the following six protected amino acids according to the sequence of amino acids Condensation of Fmoc-D-Ala-OH, Fmoc-Pro-OH, Fmoc-iLys(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Aph(Cbm)-OH and Fmoc-Aph(Hor)-OH Reaction, obtain the hexapeptide resin fragment III; S2, take CTC resin as the carrier of solid-phase synthesis, it is sequentially combined with the following four kinds of protected amino acids Fmoc-Ser(tBu)-OH, Fmoc-3-(3-pyridy )-D-Ala-OH, Fmoc-D-Phe(4-Cl)-OH and Fmoc-D-2Nal-OH carry out condensation reaction to obtain tetrapeptide...
Embodiment 1
[0050] Degarelix acetate was synthesized in this embodiment 1, and the specific process is as follows:
[0051] Synthesis of Hexapeptide Resin Fragment III:
[0052] Add 100 g of Reink amide MBHA resin with a substitution degree of 0.68mmol / g to the reaction column in turn, use DMF to swell for 30 minutes, and remove the solvent by suction filtration, then add 20wt% piperidine in DMF solution to the reaction column for Fmoc deprotection. The solution was filtered off and the resin was washed six times with DMF.
[0053] Add 42.3g Fmoc-D-Ala-OH (136mmol) and 19.3g Oxymapure (136mmol) into the four-necked flask, and add 17.2g DIC (136mmol) to activate the amino acid for 5-10min at a temperature of 0-5°C. The activated solution was transferred to the polypeptide reactor and reacted by bubbling nitrogen gas. The temperature was controlled at 20-25°C for 2 hours, and then the ninhydrin color method was used to track the reaction. If the resin was colorless and transparent, the rea...
Embodiment 2
[0069] The difference from Example 1 is: in each condensation reaction step, the ratio of protected amino acid, corresponding condensation system and Fmoc amino resin is 3:1.5:1, and the ratio of each component in the condensation system remains unchanged. The yield of the product is 86%, and the purity is 82%.
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Abstract
The invention provides a method for synthesizing Degarelix acetate. The method comprises the following steps of: S1, carrying out condensation reaction on Rink Amide MBHA resin serving as a carrier with first six amino acids of Degarelix in sequence so as to obtain a hexapeptide resin fragment III; S2, carrying out condensation reaction on CTC resin serving as a carrier with last four amino acidsof Degarelix in sequence so as to obtain a tetrapeptide resin fragment I; S3, cutting the tetrapeptide resin fragment I to obtain a tetrapeptide fragment II; S4, carrying out condensation reaction onthe hexapeptide resin fragment III and the tetrapeptide fragment II under the action of MYMsA and / or MYTsA so as to obtain a full-peptide resin; S5, cutting the whole-peptide resin to obtain Degarelix; and S6, carrying out acetic acid salt conversion on the Degarelix to obtain the Degarelix acetate. The method effectively solves the problems of multiple side reactions, low yield, high cost of a solid phase synthesis method in the preparation of Degarelix acetate.
Description
technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing degarelix acetate. Background technique [0002] Degarelix acetate is one of the main drugs for the treatment of prostate cancer. At present, Degarelix acetate is mainly obtained through solid-phase synthesis, and then converted to acetic acid to form degarelix acetate. The structure of degarelix is Ac-D-2Nal-D-Phe(4-Cl)-D-Ala(3-Pyridy)-Ser-Aph(Hor)-D-Aph(Cbm)-Leu-Lys(iPr) -Pro-D-Ala-NH 2 , the chemical formula is as follows: [0003] The traditional solid-phase synthesis method of degarelix is as follows: one-by-one amino acid synthesis is performed through a solid-phase synthesis carrier, such as patents CN102428097B, CN105085634A, etc. However, in this method, Aph(Hor) is repeatedly contacted with base, resulting in the partial conversion of dihydrouracil to hydantoin, leading to the occurrence of side reactions. [0004] In the sy...
Claims
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