Method for preparing cetrorelix acetate through specific microwave synthesis

A technology of cetrorelix acetate and microwave synthesis, which is applied in the field of polypeptide drug preparation and can solve problems such as human body injury

Inactive Publication Date: 2015-08-26
合肥国肽生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Currently, the preparation methods of cetrorelix on the market mostly adopt the liquid-phase synthesis method. These methods all use toxic reagents such as pyridine and ammonia water. Exposure to such reagents will cause great harm to the human body

Method used

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  • Method for preparing cetrorelix acetate through specific microwave synthesis
  • Method for preparing cetrorelix acetate through specific microwave synthesis
  • Method for preparing cetrorelix acetate through specific microwave synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1. Swelling of amino resin

[0026] Weigh 0.15g of Rink-AM-Resin with a degree of substitution of 0.97-1.04mmol / 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] Some commonly used abbreviations in the present invention have the following meanings:

[0033] Fmoc: fluorenylmethoxycarbonyl 3-pyridyl-D-Ala: 3-D-phenylalanine DMF: N,N-dimethylformamide

[0034] D-Cit: D-Citrulline pbf: 2,2,4,6,7-Pentameth...

Embodiment 2

[0050]The present invention has carried out the comparative experiment of the yield of cetrorelix preparation method, namely condensation reaction 1. wash after normal condensation reaction 20~30min; 20~25min after normal condensation reaction, add 0.5ml DIEA, wash after microwave amino resin 25s; The yields of the crude cetrorelix synthesized by the above experimental method were ① 82.7%, ② 91.8%. After purification and salt conversion, the pure cetrorelix acetate ① 24.1mg, ② 31.5mg were obtained. The rates are ①31.8% and ②41.2%.

Embodiment 3

[0052] The present invention has carried out secondary repeated synthesis, to confirm the stability of experimental result, condensation reaction 1. wash after 20~30min of normal condensation reaction 20~25min after normal condensation reaction, add 0.5ml DIEA, wash after microwave amino resin 25s; Obtain The purity of the crude product of cetrorelix reached 83%, and the yields of the crude product were ①83.1% and ②92.4%. After purification and salt conversion, the pure cetrorelix acetate ①24.3mg and ②31.3mg were obtained. The rate is ①32.4%, ②40.7%; confirming the correctness and stability of the experimental data of the present invention.

[0053] Through the experiment of the above-mentioned Example 2 and Example 3, it can be concluded that after normal synthesis and then microwave reaction, the yield of pure cetrorelix acetate prepared is higher and the effect is better.

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Abstract

The invention belongs to the technical field of synthesis and preparation methods of polypeptide drugs, and particularly relates to a synthesis and preparation method for cetrorelix acetate. The method is unique and exclusive. Rink Amide-AM resin is taken as a carrier, a low-cost HBTU/DIEA (hexafluorophosphate/diisopropylethylamine) is taken as a condensing agent, and a specific microwave synthesis technology is adopted, so that the condensation efficiency is improved and the crude yield reaches 92%; obtained crude cetrorelix acetate is purified with a reversed-phase high-performance liquid chromatography (rHPLC) method and subjected to acetate transformation treatment by adopting strong anion exchange resin, the yield of obtained pure cetrorelix acetate reaches more than 40%, and the acetic acid content of cetrorelix acetate reaches international standard requirements. The method greatly shortens reaction time and increases final product yield, thereby having considerable economic and applicable values and wide 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 specific microwave synthesis. 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: C70H92N17O14Cl [0006] Molecular weight: 1431.06 [0007] Cetrorelix Acetate is a potent progesterone-releasing hormone-releasing hormone (LHRH) receptor antagonist used to control ovarian stimulation to prevent premature expulsion of immature follicles and aid in conception. Due to its own physical properties (Mw value), cetrorelix Acetate is easily decomposed and destroyed by enzymes in the gastrointestinal tract, and cannot be taken orally. Therefore, it is often used as a cetrorelix preparation for injection, which can be absorbed through subcutaneou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
Inventor 陈为光孙良玉张旭光
Owner 合肥国肽生物科技有限公司
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