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Synthetic method of cetrorelix

A technology of cetrorelix and a synthesis method, applied in the field of peptide synthesis, can solve the problems of difficult fragment synthesis method, strong corrosiveness of acetic anhydride, limited access, etc., and achieves reduction of purification times, weak corrosion, and purification loss. less effect

Active Publication Date: 2021-01-01
KAIFENG MINGREN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the above-mentioned solid-phase synthesis method for preparing cetrorelix, tert-butyl isocyanate is a highly toxic substance, and the fragment synthesis method is more difficult; at the same time, acetic anhydride is used for acetylation in the current scheme, and acetic anhydride is not only highly corrosive, but also Acetic anhydride is controlled as a precursor chemical, with limited access and high price

Method used

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  • Synthetic method of cetrorelix

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The synthetic method of Cetrorelix of the present invention, the detailed steps of this synthetic method are as follows:

[0031] (1) Preparation of Fmoc-D-Ala-resin:

[0032] Soak and swell 10g of Knorr-2-Cl-Resin resin with 70ml of dichloromethane DCM for 30min to fully swell the Knorr-2-Cl-Resin resin, drain it after swelling, then add 50ml of deprotection reagent, at 25±5℃ The deprotection reaction was carried out at 25±5°C for 10 minutes, and after the reaction, it was drained, and then 50ml of deprotection reagent was added again, and it was reacted at 25±5°C for 10 minutes, and after the reaction, it was drained. Wash twice with DMF and once with DCM, each time using 50ml of detergent, drain after washing, then add 3.7g of Fmoc-D-Ala-OH (the resin refers to N-fluorenylmethoxycarbonyl-D-propane amino acid) and condensing agent, reacted at 25±5°C for 2h, and drained after the reaction, the obtained resin was washed 3 times with DMF, each time using 50ml of deterge...

Embodiment 2

[0059] The synthetic method of Cetrorelix of the present invention, the detailed steps of this synthetic method are as follows:

[0060] (1) Preparation of Fmoc-D-Ala-resin:

[0061] Soak and swell 10g of Knorr-2-Cl-Resin resin with 70ml of DCM for 30min to fully swell the Knorr-2-Cl-Resin resin, drain it after swelling, then add 50ml of deprotection reagent, and deprotect at 25±5℃ React for 10 minutes, evacuate after reaction, add 50ml of deprotection reagent again after pumping dry, react at 25±5°C for 10 minutes, dry after reaction, wash the product twice with DMF and once with DCM, each time with washing 50ml of solvent, drained after washing, then added 3.74g of Fmoc-D-Ala-OH and condensing agent, reacted at 25±5°C for 1h, and drained after reaction, the obtained resin was washed 3 times with DMF, each time with Detergent 50ml, after washing, drain to obtain Fmoc-D-Ala-resin;

[0062] The deprotection reagent used in this step is the N,N-dimethylformamide solution with ...

Embodiment 3

[0088] The synthetic method of Cetrorelix of the present invention, the detailed steps of this synthetic method are as follows:

[0089] (1) Preparation of Fmoc-D-Ala-resin:

[0090] Soak and swell 10g of Knorr-2-Cl-Resin resin with 70ml of DCM for 30min to fully swell the Knorr-2-Cl-Resin resin, drain it after swelling, then add 50ml of deprotection reagent, and deprotect at 25±5℃ React for 10 minutes, drain after reaction, add 50ml of deprotection reagent again after draining, react at 25±5°C for 10 minutes, and drain after reaction. The obtained product is washed twice with DMF and once with DCM, each time with Detergent 50ml, drained after washing, then added 3.74g Fmoc-D-Ala-OH and condensing agent, reacted at 25±5°C for 1h, and drained after reaction, the obtained resin was washed 3 times with DMF, each time Use 50ml of detergent, dry after washing to obtain Fmoc-D-Ala-resin;

[0091] The deprotection reagent used in this step is the N,N-dimethylformamide solution with...

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Abstract

The invention discloses a synthetic method of cetrorelix. According to the method, a Knorr-2-Cl-Resin resin is used as a starting raw material, and ten different amino acid resins are sequentially connected according to a solid-phase synthesis method to obtain a protected decapeptide resin. Fluorenylmethoxycarbonyl is sequentially removed during synthesis, then an N,N-dimethylformamide solution ofbenzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate and N,N-diisopropylethylamine is used as a condensation agent for carrying out a condensation reaction to obtain the protected decapeptide resin, an acetylation reaction is carried out after the condensation reaction, side chain protecting groups are removed, a cetrorelix crude product is obtained after cracking, and the obtainedcetrorelix crude product is purified to obtain a finished product. According to the synthetic method, the Knorr-2-Cl-Resin resin is used as the starting raw material, and PyBoP / DIPEA is used as the condensation reagent, so that the polypeptide sequence is easier to synthesize, and the purity of the prepared cetrorelix crude peptide is relatively high.

Description

[0001] 1. Technical field: [0002] The invention relates to the technical field of polypeptide synthesis, in particular to a synthesis method of cetrorelix. [0003] 2. Background technology: [0004] Cetrorelix is ​​a synthetic gonadotropin-releasing hormone (GnRH) antagonist (GnRH-A) drug that controls luteinizing hormone (LH) by competing with endogenous LHRH for membrane receptors on pituitary cells. and follicle stimulating hormone (FSH) secretion. For patients undergoing controlled ovarian stimulation, prevent premature ovulation, and then perform egg collection and assisted reproductive technology treatment. A large number of studies have shown that cetrorelix also has a good curative effect on ovarian cancer, prostate cancer, uterine fibroids, endometriosis and other diseases, and has a preventive effect on benign prostatic hypertrophy and ovarian hyperstimulation syndrome. [0005] Cetrorelix acetate for injection was launched in August 1999 by the original research...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/08C07K1/06C07K1/04C07K1/20
CPCC07K7/23Y02P20/55
Inventor 毛影赵冬霞李运铎刘志庆朱赞梅李沁沁娄丽丽刘美朝常欢
Owner KAIFENG MINGREN PHARMA
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