Preparation method of cetrorelix

A technology of cetrorelix and reagents, which is applied in the field of solid-phase synthesis of cetrorelix, can solve the problems of unfavorable large-scale industrial production of cetrorelix, low crude peptide yield, cumbersome process steps, etc., and achieve effective It is conducive to large-scale industrial production, has little impact on the human body and the environment, and has simple and stable processes.

Inactive Publication Date: 2015-05-13
泰州启瑞医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that after each amino acid is connected, 50% to 60% (v/v) TFA/DCM is used to remove the Boc protecting group, which will cause part of the peptide chain to fall off from the resin and reduce the final product. Yield will also cause some side chain protecting groups that are easy to acidolysis to produce side reactions
[0023] A comprehensive study of previous patent documents reveals that there are many technical problems. For example, in

Method used

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  • Preparation method of cetrorelix
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  • Preparation method of cetrorelix

Examples

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Embodiment 1

[0105] (1) Preparation of Fmoc-D-Ala-AM-resin

[0106] Weigh 1.62g (1.0mmol) Fmoc-Rink-Amide AM resin (substitution value 0.62mmol / g), place it in a jacketed 100mL polypeptide solid-phase synthesizer, add 20mL DMF to swell twice, each time for 1 hour . After the resin swelled completely, remove the DMF with a diaphragm pump, remove the Fmoc protecting group twice with 15 mL of 20% (v / v) Piperidine / DMF solution for 5 min and 15 min respectively, then wash with 20 mL of DMF for 5 times, and then remove the Fmoc protection group with a diaphragm pump. DMF was withdrawn. Dissolve 934.0mg (3.0mmol) Fmoc-D-Ala-OH and 405.3mg (3.0mmol) HOBt in 5mL DMF. After ultrasonic vibration and dissolution, ice bath for 10min, then add 560.0μL (3.6mmol) DIC, activate for 5min and mix The solution was added into a solid-phase reactor, stirred mechanically for 1 h, and the reaction temperature was controlled at 25° C. with constant temperature circulating water. The ninhydrin test was negative,...

Embodiment 2

[0122] (1) Preparation of Fmoc-D-Ala-AM-resin

[0123] Weigh 25.0g (15.5mmol) Fmoc-Rink-Amide AM resin (substitution value 0.62mmol / g), place it in a jacketed 500mL polypeptide solid-phase synthesizer, add 250mL DMF to swell twice, each time for 1 hour . After the resin swells completely, remove the DMF with a diaphragm pump, remove the Fmoc protecting group twice with 200mL 20% (v / v) Piperidine / DMF solution for 5min and 15min respectively, wash with 250mL DMF for 5 times, and then remove the Fmoc protecting group with a diaphragm pump. DMF was withdrawn. Dissolve 12.1g (38.8mmol) Fmoc-D-Ala-OH and 5.3g (38.8mmol) HOBt in 70mL DMF. After ultrasonic vibration and dissolution, ice bath for 10min, then add 7.2mL (46.5mmol) of DIC, activate for 5min The mixed solution was added into a solid-phase reactor, stirred mechanically for 1 h, and the reaction temperature was controlled at 25° C. with constant temperature circulating water. The ninhydrin test was negative, that is, the ...

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Abstract

The invention discloses a preparation method of cetrorelix. According to the preparation method, a Fmoc-Linker-amino resin is taken as the starting raw material, nine amino acids with Fmoc-protecting groups are orderly connected from the C terminal to the N terminal, and after the Fmoc-protecting groups are removed, Ac-D-2-Nal-OH is further connected to obtain an N-terminal acetylated peptide resin, namely an Ac-full-protected decapeptide resin. The peptide resin is cut by use of a cracking reagent, and the cutting fluid is precipitated by use of ice ether to obtain a cetrorelix crude peptide, and then the cetrorelix crude peptide is separated and purified by use of an HPLC preparative chromatographic column, and freeze-dried to obtain a cetrorelix trifluoroacetate or a cetrorelix acetate. According to the preparation method of the cetrorelix, the minimal protection principle is adopted, and the N-terminal acetylated amino acid Ac-D-2-Nal-OH is used for replacing Fmoc-D-2-Nal-OH in advance to avoid the side reaction of the acetic anhydride in an acetylation reagent to the D-Cit side chain carbamido; and as a result, the product purity is improved, the yield of the coarse peptide is high and large-scale industrial production can be realized favorably.

Description

technical field [0001] The invention relates to a preparation method of cetrorelix (including cetrorelix acetate, trifluoroacetate and free peptide), especially a preparation method of solid-phase synthesis of cetrorelix. Background technique [0002] Chinese common name: Cetrorelix acetate [0003] English common name: Cetrorelix Acetate [0004] Product name: Cetrotide [0005] Chemical Name: [0006] Acetyl-D-3-(2′-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3′-pyridyl)-alanine-L-serine-L-tyrosine-D-citrulline-L-leucine -L-arginine-L-proline-D-alanine-amide [0007] Amino acid sequence: [0008] Ac-D-2-Nal-D-Phe(4-Cl)-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH 2 [0009] Molecular formula: C 70 h 92 ClN 17 o 14 [0010] Molecular weight: 1431.06 [0011] CAS: 120287-85-6 [0012] Chemical Structure: [0013] [0014] Cetrorelix is ​​an antagonist of gonadotropin-releasing hormone (GnRH) for injection. It is a synthetic decapeptide containing five unnat...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 董守良姜绪邦王璐曹硕
Owner 泰州启瑞医药科技有限公司
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