Preparation method for degarelix

A technology of degarelix and solid-phase synthesis, which is applied in the field of industrialized preparation of degarelix and degarelix acetate, and can solve problems such as potential safety hazards in transportation and production processes

Inactive Publication Date: 2015-11-25
CHINESE PEPTIDE CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Currently reported degarelix Fmoc solid-phase synthesis methods have adopted HOBt or similar as amino acid coupling agent, HOBt has been classified as UN05081.3C class explosive chemicals (J.Hazard.Mater.,2005,126 ,1-7), there are potential safety hazards in the transportation and production process

Method used

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  • Preparation method for degarelix
  • Preparation method for degarelix

Examples

Experimental program
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Effect test

Embodiment 1

[0074] Step 1. FmocRinkAmide resin (800mmol, 2222g, degree of substitution 0.36mmol / g) was placed in a reactor and swelled with N,N-dimethylformamide (30L) for 30 minutes. The suspension was filtered, and 20% piperidine / N,N-dimethylformamide (30 L) was added to the resin and stirred for 30 min to remove the Fmoc protecting group. After Fmoc deprotection, the resin was washed thoroughly with N,N-dimethylformamide, ready for step 2 coupling.

[0075] Step 2. Dissolve 497.6g of Fmoc-DAla-OH, 227.4g of ethyl 2-oxime cyanoacetate (Oxyma) and 248mL of N,N-diisopropylcarbodiimide in N,N-dimethylformamide to make the amino acid Activate for 20 minutes at 0-10 degrees Celsius. After activation, the solution is added to the reactor containing the peptide resin, and the coupling reaction is carried out at 0-20 degrees Celsius for 1-4 hours, or until the ninhydrin test result is negative. The resin suspension was filtered and the peptide resin was washed with N,N-dimethylformamide. The...

Embodiment 2

[0089] Ac-D-2Nal-OH was connected by DIC / HOOBt coupling method.

[0090] Peptide Resin 1 was synthesized following steps 1 to 10 described in Example 1. The peptide resin 1 (17.2 g) obtained in step 10 above was stirred in a 20% piperidine / N,N-dimethylformamide solution for 30 minutes to remove the Fmoc protecting group. After Fmoc deprotection, the resin was washed thoroughly with N,N-dimethylformamide and was ready for coupling with Ac-D-2Nal-OH. Add 2.06g Ac-D-2Nal-OH and 1.3g HOOBt to the reactor containing the peptide resin, add an appropriate amount of N,N-dimethylformamide to dissolve the amino acid, and then add 1.24mL N,N-diisopropylcarbobis The imine is put into the reactor for the coupling reaction, and the coupling reaction is carried out at 0-20 degrees Celsius for 1-4 hours, or until the ninhydrin test result is negative. The resin suspension was filtered and washed five times with N,N-dimethylformamide and twice with methanol. After drying under vacuum, 19.85...

Embodiment 3

[0094] Ac-D-2Nal-OH was linked by DIC / HOBt coupling method.

[0095] Peptide Resin 1 was synthesized following steps 1 to 10 described in Example 1. The peptide resin 1 (0.88 g) obtained in step 10 above was stirred in a 20% piperidine / N,N-dimethylformamide solution for 30 minutes to remove the Fmoc protecting group. After Fmoc deprotection, the resin was washed thoroughly with N,N-dimethylformamide and was ready for coupling with Ac-D-2Nal-OH. 0.106 g Ac-D-2Nal-OH, 0.054 g HOBt and 0.062 mL N,N-diisopropylcarbodiimide were dissolved in N,N-dimethylformamide to activate the amino acid at 0-10 degrees Celsius for 60 minutes. After activation, the solution is added to the reactor containing the peptide resin, and the coupling reaction is carried out at 0-20 degrees Celsius for 1-4 hours, or until the ninhydrin test results are negative. The resin suspension was filtered and washed five times with N,N-dimethylformamide and twice with methanol. After drying under vacuum, 1.0 g ...

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Abstract

The invention discloses a safe, high-efficiency degarelix synthesis method, particularly a preparation method for a degarelix. With amino resin as an initial resin carrier, the method disclosed by the invention sequentially connects corresponding Fmoc-amino acids in a degarelix sequence by solid-phase synthesis, wherein Ac-D-2Nal-OH is adopted as the last amino acid, and by condensation reaction and deprotection reaction, fully protected degarelix peptide resin is obtained; acidolysis segmentation and ether sedimentation are then carried out, so that crude degarelix peptide is obtained; by chromatographic purification, acetic acid salinization and freeze drying, the acetic acid degarelix is obtained. The preparation method chooses Oxyma as safe, high-efficiency coupling reagent in order to increase the safety of the process and reduce the byproducts of the process. The process can adopt not only solid-phase synthesis but also liquid-phase synthesis, the byproducts of the process are little, and separation and purification are easy. The purity of the obtained final acetic acid degarelix product is up to 99 percent, the yield is up to 61 percent, and the final acetic acid degarelix product has considerable economically applicable value and a broad application prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a new industrial preparation process of degarelix and degarelix acetate. Background technique [0002] Degarelix (Degarelix) was developed by Ferring Pharmaceuticals (TradeName: Firmagon), approved by the US FDA, and was launched in the US on December 24, 2008, for the treatment of advanced prostate cancer. Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug that reversibly inhibits pituitary GnRH receptors to reduce gonadotropin release and thereby inhibit testosterone release. Degarelix slows the growth and progression of prostate cancer by inhibiting testosterone, which is critical for the continued growth of prostate cancer. Hormonal approaches to prostate cancer to lower testosterone levels initially caused a surge in testosterone levels, and this initial stimulation of the hormone receptor temporarily boosted rather than inhibited tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
Inventor 李湘徐琪魏忠勇
Owner CHINESE PEPTIDE CO
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