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Preparation method of degarelix

A technology of degarelix and resin, which is applied in the field of preparation of degarelix, can solve the problems of high cost of synthesis route process and difficulty in raw material synthesis, and achieve reduction of process cost and synthesis difficulty, reduction of synthesis difficulty and process cost, Simple operation effect

Inactive Publication Date: 2017-11-14
ASYMCHEM LAB TIANJIN
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The main purpose of the present invention is to provide a preparation method of degarelix to solve the problem that in the existing preparation method of degarelix, the raw materials used need to be protected by protecting groups, which will cause difficulties in the synthesis of raw materials and synthetic routes. The problem of high process cost

Method used

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  • Preparation method of degarelix

Examples

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preparation example Construction

[0032]As described in the prior art, in the existing preparation method of degarelix, the raw materials used need to be protected by protecting groups, which will cause the problems of difficult synthesis of raw materials and high cost of synthetic routes. In order to solve the above-mentioned technical problems, the application provides a preparation method of degarelix, which preparation method comprises: Fmoc-D-Ala-resin, Fmoc-Pro-OH, Fmoc-ILys (Boc )-OH, Fmoc-Leu-OH, Fmoc-D-4Aph(Cbm)-OH, Fmoc-4Nph-OH, Fmoc-Ser(tBu)-OH, Fmoc-D-3Pal-OH, Fmoc-D-Phe( 4Cl)-OH and Ac-D-2Nal-OH carry out the first condensation reaction in sequence according to the amino acid sequence of degarelix to obtain the first intermediate product; the amino acid residue 4Nph in the first intermediate product is reduced to 4Aph to obtain the first intermediate product Second intermediate product; make the side chain amino group of above-mentioned 4Aph and L-4,5-dihydroorotic acid carry out the second conden...

Embodiment 1

[0060] 1. Synthesis of Fmoc-D-Ala-Rink resin

[0061] Rink amid AM resin (10mmol, degree of substitution 0.65mmol / g) is loaded into the solid-phase reaction column, washes the above-mentioned solid-phase reaction column twice with DMF, then adds 500mL DMF to the above-mentioned solid-phase reaction column to soak Make the above resin swell, soaking time is 30min. Use 500mL of 20% DBLK to add to the above-mentioned solid-phase reaction column to wash, so as to remove part of Fmoc, and the reaction time is 10min. Then, 500 mL of 20% DBLK was added to the above-mentioned solid-phase reaction column again to remove the remaining Fmoc. The reaction time was 10 min, and then the above-mentioned solid-phase reaction column was washed 6 times with DMF.

[0062] Dissolve 9.34g Fmoc-D-Ala-OH and 8.84g HOBt in 60mL DMF to obtain a mixed solution, and cool the above mixed solution in an ice bath for 10min. Then, 5.05 g of DIC was added to the above mixture to pre-activate Fmoc-D-Ala-OH, a...

Embodiment 2

[0094] The difference from Example 1 is that the amount of reducing agent used is 3.0 times of the resin substitution degree.

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Abstract

The invention provides a preparation method of degarelix. The preparation method comprises the following steps: adopting a solid-phase synthesis method to carry out first condensation reaction on materials including Fmoc-4Nph-OH according to the amino-acid sequence of the degarelix in sequence to obtain a first intermediate product; reducing amino-acid residues 4Nph in the first intermediate product into 4Aph to obtain a second intermediate product; carrying out second condensation reaction on side-chain amino of the 4Aph and L-4, 5-dihydroorotic acid to obtain a third intermediate product; and adopting a cracking agent to crack the third intermediate product so as to obtain the degarelix. The preparation method provided by the invention has the advantages that the material Fmoc-4Nph-O is more stable under an alkali environment, and due to adoption of the material, protective groups do not need to be introduced, and side reaction caused by introduction of the protective groups is effectively avoided, so that the purity of the degarelix product can be increased; the reaction operation is simple, the reaction rate is high, and the benefit for greatly reducing the process cost and the synthesis difficulty is achieved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of degarelix. Background technique [0002] Degarelix was developed by Ferring Pharmaceuticals, approved by the US FDA, and launched in the US on December 24, 2008, for the treatment of advanced prostate cancer. [0003] Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug that reversibly inhibits pituitary GnRH receptors to reduce gonadotropin release and subsequently testosterone release. Degarelix slows the growth and progression of prostate cancer by inhibiting testosterone, which is critical for the continued growth of prostate cancer. Hormonal approaches to prostate cancer to lower testosterone levels initially caused a surge in testosterone levels, and this initial stimulation of the hormone receptor temporarily boosted rather than inhibited tumor growth, whereas degarelix did not. Phase III clinical studies have shown that the...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04
CPCC07K7/23Y02P20/55
Inventor 卢江平李九远李新勇代洪飞
Owner ASYMCHEM LAB TIANJIN
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