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Method for preparing cetrorelix

A technology for the preparation of cetrorelix, which is applied in the field of preparation of polypeptide drugs, can solve the problems of high cost, low synthetic purity, and unsuitability for industrial scale production, and achieve the effect of low cost and high purity

Inactive Publication Date: 2014-10-08
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The present inventor prepares cetrorelix with the existing synthetic method, and finds that the technical problems existing in the prior art are: synthetic purity is low, cost is high, especially all can not well control impurity [D-Cit(Ac) 6 ]-cetrorelix, not suitable for industrial scale production

Method used

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  • Method for preparing cetrorelix
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  • Method for preparing cetrorelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Preparation of Cetrorelix AM resin

[0084] Weigh 12.5g (10mol) of Rink Amide AM resin with a substitution degree of 0.80mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and swell the AM resin with DCM for 30 minutes, then use DMF:pyridine with a volume ratio of 4 :1 mixed solution to remove Fmoc protection, then wash with DMF 6 times, weigh 9.34g Fmoc-D-Ala-OH (30mmol), 4.05g HOBt (30mmol) and add DCM and DMF with a volume ratio of 1:1 to mix Solution, add 3.79g DIC (30mmol) under ice-water bath to activate, then add to the above-mentioned reaction column equipped with resin, react at room temperature for 2 hours, use ninhydrin method to detect and judge the reaction end point, if the resin is colorless and transparent, it means The reaction is complete; if the resin develops color, it means that the reaction is incomplete and needs to be reacted for another 1 hour. This judgment standard is applicable to the detection and judgment of ...

Embodiment 2

[0087] Example 2: Large-scale preparation of Cetrorelix AM resin

[0088] Weigh 125.00g (100mol) of Rink Amide AM resin with a substitution degree of 0.80mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and swell the AM resin with DCM for 30 minutes, then use DMF:pyridine with a volume ratio of 4 : 1 mixed solution to remove Fmoc protection, then wash 6 times with DMF, weigh 93.40g Fmoc-D-Ala-OH (300mmol), 40.52g HOBt (300mmol) and add DCM and DMF with a volume ratio of 1:1 to mix Solution, add 37.92g DIC (300mmol) under ice-water bath to activate, then add to the above-mentioned reaction column equipped with resin, react at room temperature for 2 hours, use ninhydrin method to detect and judge the reaction end point, if the resin is colorless and transparent, it means The reaction is complete; if the resin develops color, it means that the reaction is incomplete and needs to be reacted for another 1 hour. This judgment standard is applicable to the dete...

Embodiment 3

[0091] Example 3: Preparation of Cetrorelix Crude Peptide

[0092] Weigh 50.00g of fully protected cetrorelix crude peptide resin, add it into a 1000mL three-necked round-bottomed flask, and use TFA, Tis and H with a volume ratio of 95:2.5:2.5 2 Prepare 500 mL of the lysate composed of O, add the lysate to the above resin, react at room temperature for 2 hours, filter, wash the cleaved resin with a small amount of TFA for 3 times, combine the filtrate, concentrate, and add the concentrated liquid to glacial ether for precipitation 1 hour, centrifugal, anhydrous ether centrifugal washing 6 times, vacuum-drying, obtains cetrorelix crude peptide 145.00g, and its HPLC spectrogram is as follows figure 2 As shown, the HPLC purity was 88.86%, and the crude peptide yield was 78%.

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Abstract

The invention discloses a preparation method of cetrorelix. The method has the specific steps that: (A) AM resin is adopted as initial resin; according to cetrorelix main-chain peptide sequence, amino acids with N-terminal Fmoc protection and side-chain protection are coupled sequentially, wherein peptide sequence 6-site amino acid coupling adopts Fmoc-D-Orn(Dde)-OH; (B) when coupling is finished, Fmoc protecting group is removed, and an acetylation reaction is carried out on the N terminal; (C) a mixed solution with hydrazine hydrate and DMF with a volume ratio of 3:97 is used for removing D-ornithine side-chain Dde protecting group; tert-butyl isocyanate is added, such that D-ornithine side-chain in decapeptide resin is subjected to a modification reaction, and fully protected cetrorelix peptide resin is obtained; and (D) peptide resin is subjected to cracking, purification, desalination, and lyophilization, such that cetrorelix can be obtained. The content of a process impurity [D-Cit(Ac)<6>]-cetrorelix is less than 0.1%. The preparation process provided by the invention has the advantages of high product purity and low cost. The preparation method is suitable for large-scale cetrorelix production. With the process, the content of the impurity [D-Cit(Ac)<6>]-cetrorelix can be effectively controlled without influencing the yield of cetrorelix.

Description

technical field [0001] The invention relates to a preparation method of polypeptide drugs, in particular to a preparation method of cetrorelix. Background technique [0002] Cetrorelix, English name: Cetrorelix, is a linear polypeptide with the following structural formula: [0003] [0004] The chemical formula is as follows: [0005] Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH 2 [0006] Cetrorelix is ​​a gonadotropin-releasing hormone (GnRH) antagonist. GnRH binds to receptors on the pituitary cell membrane to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FS [0007] H) release. This product competes with endogenous GnRH for receptors on pituitary cells, thereby inhibiting the release of endogenous LH and FSH, delaying the appearance of LH peak in women, thereby controlling ovulation. This product inhibits luteinizing hormone (LH) and follicle-stimulating hormone (FS) in the pituitary gland in a dose-dependent manner. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04C07K1/107
CPCY02P20/55
Inventor 周俊路杨杨东晖周亮
Owner ADLAI NORTYE BIOPHARMA CO LTD
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