Preparation method of gabapentin acetate

A technology of ganirelix and acetic acid, applied in the field of polypeptide drug production, can solve the problems of long reaction time, large environmental pollution and low yield, and achieve the effect of long reaction time

Pending Publication Date: 2022-01-14
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, the preparation method of Ganirelix has been reported at home and abroad: as disclosed in international patents US 4801577, US 5212288, and US 5767082, it is a solid-phase synthesis method based on the Boc strategy. , not suitable for industrial production of ganirelix acetate
The solid-phase synthesis method adopted in domestic patents CN102584945A and CN110563812A 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 relatively high and easy to decompose. In the process of synthesizing the ganirelix peptide resin, multiple coupling reactions are required to complete the reaction, which takes a long time and leads to the generation of more impurities. Not conducive to industrialized scale-up production
Fmoc-Lys(Boc)-OH and Fmoc-D-Lys(Boc)-OH used in patent CN104844694A respectively replace Fmoc-HArg(Et) 2 -OH and Fmoc-D-HArg(Et) 2 -OH synthesis to obtain the crude peptide precursor, and then react with the reagent ethylaminoethyliminomethanesulfonic acid to obtain Ganyrelix. In the reaction of the modified linear peptide, it is necessary to continuously add alkali during the reaction to adjust the pH to 7.5-10.5 for the reaction , and the time used for the modified linear peptide reaction is 8.0-48.0h, the operation is cumbersome, the reaction time is long and the purity of the obtained crude peptide is not high

Method used

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  • Preparation method of gabapentin acetate
  • Preparation method of gabapentin acetate
  • Preparation method of gabapentin acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: Amino resin is coupled with amino acid to obtain linear peptide peptide resin

[0054] Put 53.5g of Rink Amide resin with a substitution degree of 0.6mmol / g into the solid-phase reaction column, swell the amino resin with DMF for half an hour, add DBLK to deprotect it for 5min+7min, wash the resin 6 times with DMF, and the ninhydrin detection resin shows that the result is positive.

[0055] Weigh Fmoc-D-Ala-OH (30.0g, 96.4mmol) and HOBt (14.3g, 106.04mmol) and dissolve them in DMF, add DIC (17.9mL, 115.6mmol) to activate for 5min, then add the mixture to the reaction column , reacted at room temperature for 2 hours, and the ninhydrin test was negative. Wash the resin 3 times with DMF, add DBLK to deprotect for 5min + 7min, wash the resin 6 times with DMF, and the ninhydrin test result is positive.

[0056] Repeat the above steps to complete Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-Tyr(tBu) sequentially by coupling one by one ...

Embodiment 2

[0057] Example 2: Acetylation of Peptide Resins

[0058] After the amino acid coupling was completed, DBLK was added for deprotection for 5min+7min, and the resin was washed with DMF for 6 times. The ninhydrin test was positive. Weigh 60.2ml of acetic anhydride and 51.7ml of pyridine and dilute with DMF to 150ml, put them into the solid-phase reaction column and react at room temperature for 2 hours. After the reaction is completed, the ninhydrin test is negative, wash with DMF for 6 times, shrink with methanol for 3 times, and vacuum dry 124.3 g of peptide resin was obtained.

Embodiment 3

[0059] Example 3: Cleavage to obtain linear peptides

[0060] Add the above-mentioned peptide resin into a 2L flask, and add the lysis reagent (TFA:H 2 O (volume ratio)=95:5, 992mL), stirred at room temperature for 2.5 hours, filtered the resin, and collected the filtrate. The resin was washed with a small amount of TFA, and the filtrates were combined. The filtrate was slowly added to 10 L of glacial ether for precipitation. Centrifuged, washed twice with ether, and dried with nitrogen gas to obtain 62.86 g of linear peptide, the purity of linear peptide was 93.70%, and the yield was 97.2%.

[0061] After detection, the linear peptide MS data of Ganirelix acetate is: 1373.561 (M+1); 1395.632 (M+1), and the HPLC spectrum is as follows figure 2 As shown, wherein the retention value T=17.738 is the target peak of the product, and the purity is 93.70%.

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Abstract

The invention discloses a preparation method of gabapentin acetate. The preparation method comprises the following steps of: 1) coupling amino resin with amino acid to obtain linear peptide resin; 2) performing acetylation reaction on the linear peptide resin obtained in the step 1); 3) cracking the linear peptide resin obtained after the acetylation reaction in the step 2) to obtain linear peptide; 4) modifying the linear peptide in the step 3) with ethylamino-1H-pyrazole under an alkaline condition to obtain crude gabapentin acetate peptide; and 5) purifying the crude gabapentin acetate peptide. According to the preparation method, the use of Fmoc-HArg (Et) 2-OH and Fmoc-D-HArg (Et) 2-OH which are high in synthesis cost and easy to decompose as raw materials is avoided, and the defects that the reaction time is long, the operation is complicated and the purity of the obtained crude peptide is not high due to the fact that alkali needs to be continuously added to adjust the pH to 7.5-10.5 for reaction in the reaction process are overcome.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug production, and relates to a preparation method of ganirelix acetate. Background technique [0002] Ganirelix acetate is an antagonist of gonadotropin-releasing hormone (GnRH), which inhibits the secretion of LH from the pituitary gland more significantly than the secretion of FSH, thereby reducing the production of sex hormones. For women with ovarian hyperstimulation, this product can prevent LH fluctuations and related stimulation, and improve the rate of implantation and pregnancy. Therefore, ganirelix acetate has high medicinal value and broad market prospects. Ganirelix Acetate Injection was developed and produced by Merck & Co., and was launched in the United States in 1999. It was approved by the State Food and Drug Administration of China to be launched in China in 2013 under the product name ORGALUTRAN. The structure of Ganyrelix contains 10 amino acids, and the peptide sequen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/04
CPCC07K7/23Y02P20/55
Inventor 汪龙陶志强尹传龙唐洋明余品香
Owner HYBIO PHARMA
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