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Preparation method of key intermediate of degarelix

A synthetic method and technology of Rick polypeptide, applied in chemical instruments and methods, luteinizing hormone releasing hormone, peptides, etc., can solve the problem of no degarelix polypeptide fragments, etc., and achieve the effect of avoiding racemization

Active Publication Date: 2018-04-24
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] There is no relevant report on the synthesis of the above-mentioned degarelix polypeptide fragments in the prior art, and it is urgent to develop a method for preparing the above-mentioned degarelix polypeptide fragments with high purity and high yield

Method used

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  • Preparation method of key intermediate of degarelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] H-Lys(iPr, Boc)-Pro-D-Ala-NH 2 +Fmoc-Leu-OH→Fmoc-Leu-Lys(iPr, Boc)-Pro-D-Ala-NH 2

[0027] L-lysyl-N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide (45.5g, 1eq), Fmoc- Add L-leucine (38.8g, 1.1eq), HOBT (14.9g, 1.1eq), N,N-dimethylformamide 200ml, tetrahydrofuran 600ml into the reaction flask, stir and control the temperature at 10-20°C and add N- After methylmorpholine (10 g, 1.0 eq), triethylamine (10 g, 1.0 eq), EDC·HCl (22.9 g, 1.2 eq) was added and stirring continued for 4 hours.

[0028] After the reaction was completed, 1.5 L of water and 3.0 L of ethyl acetate were added to the reaction solution for extraction. The organic phase was washed once with 1.5 L of water, dried by adding anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain Fmoc-L-leucyl- N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide crude product 67.1g, yield 85.1%. HPLC detection showed that the content of rac...

Embodiment 2

[0031]L-lysyl-N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide (45.5g, 1eq), Fmoc- Add L-leucine (38.8g, 1.1eq), HOBT (14.9g, 1.1eq), N,N-dimethylformamide 200ml, tetrahydrofuran 600ml into the reaction flask, stir and control the temperature at 10-20°C and add N- After methylmorpholine (10g, 1.0eq), triethylamine (10g, 1.0eq), bis-p-fluorophenylcarbodiimide (27.6g, 1.2eq) was added and stirring was continued for 4 hours.

[0032] After the reaction was completed, 1.5 L of water and 3.0 L of ethyl acetate were added to the reaction solution for extraction. The organic phase was washed once with 1.5 L of water, dried by adding anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain Fmoc-L-leucyl- N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide crude product 67.1g, yield 85.1%. HPLC detection showed that the content of racemic peptide was 0.05%, the total impurity was 0.87%, and the maximum sing...

Embodiment 3

[0035] L-lysyl-N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide (45.5g, 1eq), Fmoc- Add L-leucine (38.8g, 1.1eq), HOBT (14.9g, 1.1eq), N,N-dimethylformamide 200ml, tetrahydrofuran 600ml into the reaction flask, stir and control the temperature at 10-20°C and add N- After methylmorpholine (10 g, 1.0 eq), triethylamine (10 g, 1.0 eq), DCC (24.7 g, 1.2 eq) was added and stirring was continued for 4 hours.

[0036] After the reaction was completed, 1.5 L of water and 3.0 L of ethyl acetate were added to the reaction solution for extraction. The organic phase was washed once with 1.5 L of water, dried by adding anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain Fmoc-L-leucyl- N6-(1-isopropyl-1-tert-butoxycarbonyl)-L-lysyl-L-prolyl-D-alaninamide crude product 65.6g, yield 83.1%. HPLC detection showed that the content of racemic peptide was 0.24%, the total impurity was 1.47%, and the largest single impurity was 0.33...

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Abstract

The invention relates to a preparation method of a key intermediate of degarelix. The preparation method comprises that L-lysyl-N6-(1-isopropyl-1-t-butyloxycarboryl)-L-lysyl-L-prolyl-D-alaninamide andFmoc-L-leucine react in the mixed solution of N, N-dimethylformamide and tetrahydrofuran with the presence of organic alkali and a condensing agent to obtain the peptide fragment of the degarelix ofFmoc-L-leucine-N6-(1-isopropyl-1-t-butyloxycarboryl)-L-lysyl-L-prolyl-D-alaninamide. The preparation method of the key intermediate of the degarelix can reduce racemization during peptide condensationand prepare the peptide fragment of the degarelix at high purity and high yield.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing a key intermediate for preparing the decapeptide degarelix. Background technique [0002] Prostate cancer is the leading cause of morbidity and mortality in men in the industrialized world. Degarelix, also known as FE200486, is a third-generation gonadotropin-releasing hormone (GnRH) receptor antagonist (GnRH blocker) that has been developed and recently approved for use in patients requiring androgen blockade therapy for prostate cancer patients. Degarelix acts by directly and competitively blocking GnRH receptors in the pituitary gland and, like other GnRH antagonists, does not cause an initial stimulation of luteinizing hormone production via the hypothalamic-pituitary-gonadal axis , and therefore does not cause a testosterone surge or clinical outburst. [0003] Degarelix is ​​a synthetic linear decapeptide containing seven unnatural amino acids,...

Claims

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Application Information

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IPC IPC(8): C07K5/103C07K7/23
CPCC07K5/101C07K7/23
Inventor 许春敏陈之峰张庆捷
Owner 连云港恒运药业有限公司
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