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Preparation method of vilacatide impurities

A technology of veracatide and impurities, which is applied in the field of preparation of impurities, and can solve problems such as toxicity, adverse reactions, and generation of degraded impurities

Pending Publication Date: 2020-11-13
HAINAN ZHONGHE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the chemical structural properties of veracapide, it may generate degradation impurities during storage, and these impurities may cause allergic reactions, toxicity and other adverse reactions

Method used

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  • Preparation method of vilacatide impurities
  • Preparation method of vilacatide impurities
  • Preparation method of vilacatide impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: the preparation of impurity I [Des-Ac]

[0078] Weigh 10.6g of Rink Amide AM resin (10mmol, substitution value 0.95mmol / g), add to the peptide synthesis reaction column, add 90ml of DCM to swell for 30min, and drain. Add 20% PIP / DMF to remove Fmoc protection twice (the time is 5min+10min respectively), and wash with DMF for 6 times until the pH value of the washing solution is 6.5-7.0.

[0079] Coupling reaction: Weigh 19.46g Fmoc-Arg(pbf)-OH (3.0eq), 5.40g HOBt (4.0eq) and dissolve in 50ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃ to activate After 5 minutes, add it to the synthesis reaction column, stir and react at 30°C±3°C for 2-3h, when the ninhydrin test is negative, drain it, and wash it with DMF for 3 times.

[0080] Deprotection reaction: add 20% PIP / DMF to remove Fmoc protection twice (5min+10min respectively), wash with DMF 6 times, until the pH value of the washing solution is 6.5-7.0.

[0081] Repeat the steps of coupling reaction and deprotectio...

Embodiment 2

[0085] Embodiment 2: Impurity II [Arg 7 -OH] Preparation

[0086] Weigh 12.5g of Wang resin (10mmol, substitution value: 0.80mmol / g), add to the peptide synthesis reaction column, add 90ml of DCM to swell for 30min, and drain. Wash twice with DMF and drain.

[0087] Coupling reaction: Weigh 19.46g Fmoc-Arg(pbf)-OH(3.0eq), 5.40g HOBt(4.0eq), 0.37g DMAP(0.3eq) and dissolve in 50ml DMF, add at 0℃~10℃ 6.2ml of DIC (4.0eq), activated for 5min, added to the synthesis reaction column, stirred and reacted at 30°C±3°C for 3-4h. Drained and washed 3 times with DMF.

[0088] Deprotection reaction: add 20% PIP / DMF to remove Fmoc protection twice (5min+10min respectively), wash with DMF 6 times, until the pH value of the washing solution is 6.5-7.0.

[0089] Repeat the steps of coupling reaction and deprotection reaction, sequentially coupling Fmoc-D-Ala-OH, Fmoc-Arg(pbf)-OH, Fmoc-Arg(pbf)-OH, Fmoc-Arg(pbf)-OH, Fmoc -D-Ala-OH, Fmoc-D-Cys(Trt)-OH, to get D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-A...

Embodiment 3

[0093] Embodiment 3: the preparation of impurity III [D-Cys(Cys(S=O))]

[0094]Weigh 10.6g Rink Amide AM resin (10mmol, substitution value 0.95mmol / g), add to the peptide synthesis reaction column, add 70ml DCM to swell for 30min, and drain. Wash twice with DMF and drain. Add 20% PIP / DMF to remove Fmoc protection twice (the time is 5min+10min respectively), and wash with DMF for 6 times until the pH value of the washing solution is 6.5-7.0.

[0095] Coupling reaction: Weigh 19.46g Fmoc-Arg(pbf)-OH (3.0eq), 5.40g HOBt (4.0eq) and dissolve in 50ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃ to activate After 5 minutes, add it to the synthesis reaction column, stir and react at 30°C±3°C for 2-3h, when the ninhydrin test is negative, drain it, and wash it with DMF for 3 times.

[0096] Deprotection reaction: add 20% PIP / DMF to remove Fmoc protection twice (5min+10min respectively), wash with DMF 6 times, until the pH value of the washing solution is 6.5-7.0.

[0097] Repeat the steps ...

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Abstract

The invention discloses a preparation method of five vilacatide impurities. The structures of the five impurity peptide sequences are respectively as follows: an impurity I: D-Cys (Cys)-D-Ala-D-Arg-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2; an impurity II: Ac-D-Cys (Cys)-D-Ala-D-Arg-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-OH; an impurity III: Ac-D-Cys (Cys (S = O))-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2; an impurity IV: Ac-D-Cys (S = O) (Cys)-D-Ala-D-Arg-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2; and an impurity V. A high-purity impurity sample can be obtained by adopting the preparation method disclosed by the invention, and the HPLC purity is higher than 96.0%. The five vilacatide impurities involved in the invention are potential degradation impurities, and a reliable impurity reference substance is provided for quality research of vilacatide bulk drugs and vilacatide injections so as to ensure the product quality.

Description

technical field [0001] The invention relates to an impurity of active polypeptide medicine and a preparation method thereof, in particular to a preparation method of the impurity. Background technique [0002] Etelcalcetide is a novel calcimimetic agent developed by AMGMN INC. It is mainly used as a polypeptide drug for secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing hemodialysis. It was launched in the United States on February 07, 2017, under the product name Parsabiv. Clinical data show that veracatide is as good as cinacalcet in reducing parathyroid hormone levels in secondary hyperparathyroidism, and because it can be administered intravenously after hemodialysis, it is superior to existing The standard calcimimetic treatment is cinacalcet. [0003] The main chain of verakatide is composed of 7 amino acids, but all of them are unnatural amino acids D-type amino acids, which are 4 D-Arg, 2 D-Ala and 1 D-Cys respectively. L-cystei...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/08C07K1/06C07K1/04C07K1/20G01N33/68
CPCC07K7/06G01N33/94G01N33/68
Inventor 陈超周良凌振宏云晓
Owner HAINAN ZHONGHE PHARM CO LTD
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