A kind of method of synthesizing cetrorelix

A technology of cetrorelix and condensation reagents, which is applied in the field of synthesizing cetrorelix, can solve the problems that the total yield cannot be increased, and achieve the effects of mild conditions, high total yield and high product quality

Active Publication Date: 2021-04-20
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, on the one hand, it uses toxic hydrazine hydrate to remove the D-Orn (Dde) side chain protecting group Dde; on the other hand, the traditional trifluoroacetic acid lysis solution cannot completely remove the fully protected cetrirelactide resin, resulting in a The yield cannot be improved; the third aspect is still unable to completely avoid the occurrence of toxic impurity [D-Cit(Ac)]-cetrorelix

Method used

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  • A kind of method of synthesizing cetrorelix
  • A kind of method of synthesizing cetrorelix
  • A kind of method of synthesizing cetrorelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: the synthesis of D-Ala-MOBHA resin

[0050] Take 0.15mol Fmoc-D-Ala and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, and slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid. Amino acid solution, spare.

[0051] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-D-Ala solution, stir at room temperature for 3 hours, remove the reaction solution, and wash with DMF for 3 times Finally, DCM was washed 3 times, and the washing time was 3 minutes each time to obtain Fmoc-D-Ala-MOBHA resin, which was deprotected with 20% PIP / DMF solution for 25 minutes, washed and filtered to obtain D-Ala-MOBHA resin.

Embodiment 2

[0052] Embodiment 2: the synthesis of D-Ala-MOBHA resin

[0053] Take 0.15mol Boc-D-Ala and 0.15mol HOBt, and dissolve them with appropriate amount of DMF; take another 0.15mol DIC, slowly add it into the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid. Amino acid solution, spare.

[0054] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-D-Ala solution, stir at room temperature for 3 hours, remove the reaction solution, and wash with DMF for 3 times Finally, wash with DCM 3 times, each washing time is 3min, to obtain Boc-D-Ala-MOBHA resin, deprotect with 30% TFA / DCM solution for 30 minutes, neutralize with DIEA / DCM solution, wash and filter with DMF and DCM D-Ala-MOBHA resin was obtained.

Embodiment 3

[0055] Embodiment 3: the synthesis of Pro-D-Ala-MOBHA resin

[0056] Take 0.15mol Fmoc-Pro and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution .

[0057] Add the above-mentioned activated protected amino acid solution to the D-Ala-MOBHA resin prepared in Example 1, stir and react at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, and wash 3 times with DCM, each washing time is After 3 minutes, deprotect with 20% PIP / DMF solution for 25 minutes, wash and filter to obtain Pro-D-Ala-MOBHA resin.

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Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthesizing cetrorelix. The present invention adopts a brand-new amino resin as a carrier, and adopts protected D-Orn as the precursor of D-Cit, then removes the side chain protecting group and reacts with tert-butyl isocyanate to generate D-Cit (tBu), through the unique containing Hydrogen bromide trifluoroacetic acid solution to acid hydrolyze the cetrorelix peptide resin, and simultaneously remove the side chain protecting group tBu of the generated D-Cit(tBu) to the greatest extent, and the finally obtained cetrorelix has a higher The purity and total yield avoid the generation of toxic impurity [D-Cit(Ac)]-cetrorelix, the whole method is simple and easy to operate, the conditions are mild, and the product quality is high.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing cetrorelix. Background technique [0002] Cetrorelix is ​​a gonadotropin-releasing hormone (GnRH) antagonist. GnRH binds to receptors on the pituitary cell membrane to stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Cetrorelix competes with endogenous GnRH for receptors on pituitary cells, thereby inhibiting the release of endogenous LH and FSH. The inhibitory effect of cetrorelix occurs immediately after injection and there is no stimulatory effect. In women, cetrorelix works by delaying the onset of the LH surge, thereby controlling ovulation. The effect of cetrorelix is ​​dose-dependent, 3 mg of cetrorelix can maintain the drug effect for 4 days, and the inhibitory effect on the 4th day is about 70%. Injection of cetrorelix 0.25 mg every 24 hours can make the inhibitory effect sustained. Animal exp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCC07K7/23Y02P20/55
Inventor 马中刚郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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