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Preparation method of solid phase synthesis cetrorelix

A technology of solid-phase synthesis and cetrorelix, which is applied in the field of preparation of cetrorelix acetate, can solve problems such as environmental pollution and high cutting toxicity, and achieve the effects of stable process, low production cost and high yield

Active Publication Date: 2008-10-15
滨海吉尔多肽有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0039] The purpose of the present invention is to provide a preparation method of cetrorelix, which mainly solves the technical problem of environmental pollution caused by the high toxicity of cutting the resin by using HF in the existing solid phase synthesis method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1) Preparation of Fmoc-D-Aal-resin

[0051]Soak Fmoc-linker-MBHA-resin with DCM for 2-5 times to fully swell the resin, add decapping reagent, react, drain, wash with DMF, drain, add Fmoc-D-Ala-OH dissolved in peptide reagent , the mixture of HBTU / HOBT / DIEA, 35-50°C for 2 hours to react with peptide, then drained, the resin was washed with DMF, and vacuum-dried to obtain Fmoc-D-Aal-resin.

[0052] The component and volume ratio of said decapping reagent are 20% Piperidine DMF,

[0053] The number of moles of Fmoc-D-Ala-OH is twice that of the resin, the same below,

[0054] The ratio of the weight of the Fmoc-linker-MBHA-resin resin to the amount of decapping reagent added is 8-15ml / g resin, the same below,

[0055] The mole number of HBTU is twice that of the resin, the same below.

[0056] The mole number of HOBT is twice that of the resin, the same below.

[0057] The number of moles of DIEA is 4 times that of the resin, the same below.

[0058] (2) Preparation...

Embodiment 2

[0096] (1) Preparation of Fmoc-Pro-D-Aal-resin

[0097] In 1 gram of Fmoc-D-Aal-resin in step (1) of Example 1, add decapping reagent, decapping reaction at 35-50°C for 20-30 minutes, drain, wash 3 times with DMF, MeOH, DCM successively, Drain, add Fmoc-Pro-OH dissolved in peptide reagent, DIC / HOBT / DIEA mixture, react with peptide at 30-50°C for 0.5 hours, drain, wash with DMF and dry to obtain Fmoc-Pro-D- Aal-resin.

[0098] The component and volume ratio of said decapping reagent are 20% Piperidine DMF,

[0099] The mole number of Fmoc-Pro-OH is 4 times that of the resin.

[0100] The number of moles of DIC is twice that of the resin, the same below.

[0101] The mole number of HOBT is twice that of the resin, the same below.

[0102] The number of moles of DIEA is 4 times that of the resin, the same below.

[0103] (2) Preparation of Fmoc-Arg(pbf)-Pro-D-Aal-resin

[0104] In the Fmoc-Pro-D-Aal-resin of step (1), add decapping reagent, 35-50 ℃ decapping reaction for 20...

Embodiment 3

[0139] According to the present invention, the method for crude product separation and purification through C18 (C8) column comprises the steps:

[0140] Dissolve the crude cetrorelix acetate in acetonitrile / water solution, filter, and purify the filtrate through C18 or C8 column, mobile phase: phosphate or trifluoroacetate: acetonitrile (0.1-100:100-0.1 volume ratio); detection The wavelength is 220nm; the required effluent is tracked and collected with a liquid chromatograph, the sample peaks are combined, desalted, and freeze-dried to obtain a finished product with a total yield of 20% (in mmol of the resin). The weight concentration of the acetonitrile is 0.5-10%, and the weight concentration of the cetrorelix acetate in the acetonitrile is 1-10%.

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Abstract

A method for realizing the solid phase synthesis of cetrorelix comprises the following steps that: Fmoc-Linker-MBHA-Resin is used as a starting raw material and is connected in turn with amino acid with Fmoc-protecting groups according to a solid phase synthesis method, so as to obtain protective decapeptide resin; meanwhile, the Fmoc-protecting groups are divested in turn; one sort of HBTU / HOBT or DIC / HOBT is used as condensing agent to carry out synthesized peptide, thereby obtaining protective decapeptide resin; acetylation reaction is carried out, and then protecting group side chain divesting and peptide cutting are carried out synchronously to obtain cetrorelix acetate which is separated and purified through C18 or C8 chromatographic column; finally, cetrorelix acetate acetate or trifluoroacetate is obtained after freeze drying.

Description

Technical field: [0001] The invention relates to a preparation method of cetrorelix acetate (including acetate, trifluoroacetate and free peptide), especially a preparation method of solid-phase polypeptide synthesis of cetrorelix. Background technique: [0002] Chinese name: Cetrorelix acetate [0003] English name: Cetrorelix Acetate [0004] Structural formula: [0005] AC-3-(2-naphthyl) [0006] -D-Ala-4-Chloro-D-Phe-3(3-Pyriclyl-D-Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2 [0007] Molecular formula and molecular weight: C70H92N17O14CL 1430.1 [0008] Cetrorelix Acetate is a gonadotropin-releasing hormone used to stimulate regulated ovaries prior to infertility treatment. The main treatment is gonadotropin-releasing hormone receptor blockade. [0009] The effect of LHRH antagonist Cetrorelix on the growth cycle and cycle-related proteins of endometrial cancer cells, and to explore its mechanism of inhibiting the growth of endometrial cancer cells [0010] Solvay, a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/04C07K1/06C07K1/20
CPCY02P20/55
Inventor 徐红岩金健林袁莹葛刚
Owner 滨海吉尔多肽有限公司
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