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Ganirelix acetate preparation method

A technology of Ganirelix and acetic acid, which is applied in the field of drug synthesis, can solve problems such as increased side reactions, non-reaction, and large environmental pollution, and achieve the effects of suppressing side reactions, increasing yield, and reducing pollution

Inactive Publication Date: 2015-08-19
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The Boc solid-phase synthesis method adopted in US5767082 needs to use HF for cracking, which is very polluting to the environment and is not conducive to production
The Fmoc solid-phase synthesis method adopted by CN102584945A needs to use Fmoc-HArg(Et) 2 -OH and Fmoc-D-HArg(Et) 2 -OH is the raw material. The synthesis cost of these two amino acids is high, which is not conducive to large-scale production. In addition, these two amino acids are easy to decompose, and after they are connected to the resin, they need to go through multiple coupling reactions, resulting in more impurities.
[0007] In addition, the current methods for synthesizing ganirelix acetate all use organic solvents as solvents, which cannot accurately and real-time monitor the pH value during the reaction process, which may easily lead to the failure of the reaction or the increase of side reactions, thereby reducing the content of the product in the crude peptide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Synthesis of Ganyrelix Precursor I

[0039] 1. Preparation of Fmoc-D-Ala-Rink Amide resin

[0040] 40 g of Rink Amide resin with a substitution degree of 0.5 mmol / g was loaded into a solid-phase reaction column, washed twice with DMF, swollen with DMF for 30 minutes, deprotected twice for 10 minutes and 15 minutes respectively, washed with DMF for 6 times, Ninhydrin test was positive.

[0041] Fmoc-D-Ala-OH (18.68g, 60mmol) and HOBt (8.52g, 63mmol) were dissolved in 150ml DMF, and DIC (9.9ml, 63mmol) was added to activate for 5 minutes under ice-cooling conditions, and the activated solution was added Into the solid-phase reaction column, nitrogen stirring reaction for 2 hours, ninhydrin detection was negative. Drain the reaction solution, wash with DMF three times, deprotect DBLK twice for 5 minutes and 7 minutes respectively, wash with DMF for 6 times, and the ninhydrin test is positive.

[0042] 2. Coupling of other amino acids of the Fomc protecting gr...

Embodiment 2

[0049] Embodiment 2: Synthesis of Ganirelix Crude Product

[0050] The ganirelix precursor I (3.1 g, 2 mmol) obtained in Example 1 and ethylaminoethyleneimino methanesulfonic acid (0.72 g, 4 mmol) were dissolved in 20 ml H 2 In O, 10% NaOH was slowly added dropwise at room temperature to adjust the pH to 7.5, mechanically stirred for 8 hours, and 10% NaOH was added during the reaction to maintain the pH at 7.5, and the product purity in the reaction solution was 35%.

Embodiment 3

[0051] Embodiment 3: the synthesis of Ganirelix crude product

[0052] The ganirelix precursor I (3.1 g, 2 mmol) obtained in Example 1 and ethylaminoethyleneimino methanesulfonic acid (0.72 g, 4 mmol) were dissolved in 20 ml H 2 In O, 10% NaOH was slowly added dropwise at room temperature to adjust the pH to 9.0, and the reaction was carried out with mechanical stirring for 8 hours. During the reaction, 10% NaOH was added to maintain the pH at 9.0, and the product purity in the reaction solution was 41%.

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Abstract

The present invention belongs to the technical field of drug synthesis, and discloses a ganirelix acetate preparation method, wherein Fmoc-Lys (Boc)-OH and Fmoc-D-Lys (Boc)-OH are adopted to respectively replace Fmoc-HArg (Et)2-OH and Fmoc-D-HArg (Et)2-OH, a ganirelix precursor I is previously synthesized, and the side chain amino of Lys and D-Lys in the precursor I is modified and treated so as to obtain the ganirelix acetate. According to the present invention, water is adopted to replace the organic solvent and is adopted as the reaction solvent, such that the reaction can be performed within the established pH value range, and the product content in the crude peptide is significantly improved; and the product yield can be significantly improved through the HPLC two-step purification method.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of ganirelix acetate. Background technique [0002] Ganirelix acetate, the English name is Ganirelix acetate; the chemical name is N-acetyl-3-(2-naptyl)-D-alanyl-4-chloro-D-phnylalanyl-3-(3-pyridyl)-D-alanyl -L-tyrosyl-N 9 ,N 10 diethyl-D-homoarginyl-L-leucyl-N 9 ,N 10 -diethyl-L-homoargin yl-L-prolyl-D-alanylamide acetate; Molecular formula is C 80 h 113 ClN 18 o 13 ; The relative molecular mass is 1570.3; the CAS registration number is 123246-29-7. Its chemical structure is shown in the following formula: [0003] [0004] Ganirelix acetate is a synthetic decapeptide compound similar to endogenous gonadotropin-releasing hormone (GnRH) (also known as luteinizing hormone-releasing hormone, LHRH), and is an antagonist of GnRH, which can competitively antagonize The gonadotropic GnRH receptors, thereby mutating pathways, cause rapid, reversi...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/04C07K1/16
CPCY02P20/55
Inventor 陈友金尹传龙刘建马亚平袁建成
Owner HYBIO PHARMA
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