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Method for preparing cetrorelix acetate by taking Rink Amide-AM Resin as carrier

A technology of cetrorelix acetate and cetrorelix, which is applied in the field of polypeptide drug preparation and can solve the problems of great harm to human body and the like

Inactive Publication Date: 2015-01-14
BIOTECH CO LTD QINGDAO BEI TAIKE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the preparation methods of cetrorelix described above, relatively toxic reagents are used. If they are used in the large-scale preparation of cetrorelix, they will be exposed to such reagents for a long time, which will cause great harm to the human body.

Method used

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  • Method for preparing cetrorelix acetate by taking Rink Amide-AM Resin as carrier
  • Method for preparing cetrorelix acetate by taking Rink Amide-AM Resin as carrier
  • Method for preparing cetrorelix acetate by taking Rink Amide-AM Resin as carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1. Swelling of amino resin

[0026] Weigh 0.16g of Rink-AM-Resin with a degree of substitution of 0.3-0.87mmol / g, add it to the polypeptide synthesis reactor from the open end, take the DCM reagent and add it to the reactor, so that the resin is completely immersed in the DCM solvent. Fully exposed to the solvent, swelling for 2h.

[0027] 2. Synthesis of Fmoc-cetrorelix resin

[0028] The cetrorelix precursor peptide I-amino resin is:

[0029] Fmoc-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-Amino Resin

[0030] The protected amino acids used in this example are listed in the table below for the protected amino acids and molecular weights corresponding to the 1st to 10th amino acids from the resin:

[0031]

[0032]

[0033] Some commonly used abbreviations in the present invention have the following meanings:

[0034] Fmoc: fluorenylmethoxycarbonyl pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0035] D-Cit: D-citrulline tBu: tert-butyl 3-py...

Embodiment 2

[0052] The present invention has carried out the comparative experiment of the yield of the preparation method of cetrorelix, namely condensation reaction 1) washing after normal condensation reaction 20-50min; 25-30min after normal condensation reaction, adding 0.5ml DIEA, and washing after microwave amino resin The yield of the cetrorelix crude product synthesized through the above-mentioned experimental method is ① 92.7%, ② 95.2%, and the cetrorelix acetate pure product ① 23.3mg, ② 25.8mg are obtained through purification and salt conversion. Product yields were ①30.8%, ②34.1%.

Embodiment 3

[0054] In order to determine the stability of the experimental results, the present invention has carried out two times of repeated synthesis, condensation reaction ① normal condensation reaction 20 ~ 50min after washing ② normal condensation reaction 25 ~ 30min, add 0.5ml DIEA, microwave amino resin after 10 ~ 20s Washing; the purity of the cetrorelix crude product is 78-85%, the yield of the crude product is 1.93.7%, 2.94.98%, and the pure cetrorelix acetate 1.31.7mg, 2.34. 76mg, the pure product yields are ①31.01%, ②34.0%; confirm the correctness and stability of the experimental data of the present invention.

[0055] According to the above experiments in Example 2 and Example 3, it can be concluded that the pure product of cetrorelix acetate prepared by microwave after normal synthesis has higher yield and better effect.

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Abstract

The invention belongs to the technical field of preparation methods of polypeptide medicaments and particularly relates to a preparation method of cetrorelix acetate. According to the preparation method provided by the invention, Rink Amide-AM Resin is taken as a carrier, low-cost DIC / HOBt is taken as a condensation agent, and a unique microwave reaction technology is adopted, so that the reaction time is shortened, the condensation efficiency is improved, and the yield of a crude product is more than 90%. The obtained cetrorelix acetate crude product is subjected to reversed-phase high performance liquid chromatography purification and treated by a unique technology for converting acetate to salt, so that the yield of an obtained pure product of cetrorelix acetate is more than 30%, and the toxicity of trifluoroacetic acid to an organism is thoroughly removed. The preparation method provided by the invention optimizes the condensation reaction step, a polypeptide synthesis process is simple and easy to operate, the production cost is low, and the product yield is high, so that the preparation method has considerable economic applicable values and extensive application prospects.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a method for preparing cetrorelix acetate by using Rink Amide-AM Resin as a carrier. Background technique [0002] Chinese name: Cetrorelix acetate [0003] English name: cetrorelix Acetate [0004] Structural formula: Ac-D-2-Nal-D-Cpa-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2 [0005] Molecular formula and molecular weight: C70H92N17014C1 1431.06 [0006] Cetrorelix Acetate, also commonly known as cetrorelix, is an effective progesterone-releasing hormone (LH-RH) receptor antagonist, which can control ovarian stimulation and prevent infertility. Mature follicles are released prematurely to help conception, so it is often used as a cetrorelix preparation for injection. [0007] The anticancer drug cetrorelix, a newly synthesized gonadotropin-releasing hormone (GNRH) antagonist, controls luteinizing hormone (LH) and follicle stimulation by compet...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/20C07K1/06C07K1/04
Inventor 陆之贤陈为光郑范娜杨慧丁彦伟
Owner BIOTECH CO LTD QINGDAO BEI TAIKE
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