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Preparation method of atosiban acetate impurities

A technology for atosiban acetate and impurities, which is applied in the field of preparation of atosiban acetate impurities, and can solve problems such as toxicity, adverse reactions, and allergic reactions

Pending Publication Date: 2019-09-10
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 structure of atosiban acetate, it may produce 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 atosiban acetate impurities
  • Preparation method of atosiban acetate impurities
  • Preparation method of atosiban acetate impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: Impurity I [Asp 5 ,Gly 9 -OH] Preparation

[0068] 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. Weigh 8.92g Fmoc-Gly-OH (3.0eq), 5.40g HOBt (4.0eq), 0.37g DMAP (0.3eq) and dissolve in 50ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃ , activated for 5 minutes, added to the synthesis reaction column, stirred and reacted at 30°C±3°C for 3-4h. Drained and washed 3 times with DMF. Add 20% PIP / DMF to remove Fmoc protection twice (the time is 5min+10min respectively), and wash with DMF 6 times.

[0069]Weigh 13.63g Fmoc-Orn(Boc)-OH (3.0eq), 5.40g HOBt (4.0eq) and dissolve in 50ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃, activate for 5min, add In the synthesis reaction column, stir and react at 30°C±3°C for 2-3 hours, and the ninhydrin test is negative. Drained and washed 3 times with DMF. Add 20% PIP / DMF to remove Fmoc p...

Embodiment 2

[0073] Embodiment 2: Impurity II [Orn(Ac) 8 ] preparation

[0074] 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 6 times.

[0075] Weigh 8.92g Fmoc-Gly-OH (3.0eq), 5.40g HOBt (4.0eq) and dissolve in 40ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃, activate for 5min, add to the synthesis reaction column During the reaction at 30°C±3°C for 2 to 3 hours with stirring, the ninhydrin test was negative. Drained and washed 3 times with DMF. Add 20% PIP / DMF to remove Fmoc protection twice (the time is 5min+10min respectively), and wash with DMF 6 times.

[0076] Repeat the above steps and sequentially couple Fmoc-Orn(Ac)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc -Ile-OH, Fmoc-D-Tyr(Et)-OH, Mpa(Trt)-OH....

Embodiment 3

[0079] Example 3: Preparation of Impurity III [Dimer 1]

[0080] 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 6 times.

[0081] Weigh 8.92g Fmoc-Gly-OH (3.0eq), 5.40g HOBt (4.0eq) and dissolve in 40ml DMF, add 6.2ml DIC (4.0eq) at 0℃~10℃, activate for 5min, add to the synthesis reaction column During the reaction at 30°C±3°C for 2 to 3 hours with stirring, the ninhydrin test was negative. Drained and washed 3 times with DMF. Add 20% PIP / DMF to remove Fmoc protection twice (the time is 5min+10min respectively), and wash with DMF 6 times.

[0082] Repeat the above steps and sequentially couple Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc -Ile-OH, Fmoc-D-Tyr(Et)-OH, Mpa(Acm)-OH. ...

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Abstract

The invention discloses a preparation method of four atosiban acetate impurities. The peptide sequence structure of the impurity I is c[Mpa-D-Tyr(Et)-Ile-Thr-Asp-Cys]-Pro-Orn-Gly-OH, the peptide sequence structure of the impurity II is c[Mpa-D-Tyr(Et)-Ile-Thr-Asn-Cys]-Pro-Orn(Ac)-Gly-NH2, and the peptide sequence structures of the impurity III and the impurity IV are shown in the description. By means of the preparation method, high-purity impurity samples can be obtained, and the HPLC purities are all higher than 96.0%. The four atosiban acetate impurities are all potential degradable impurities and provide reliable impurity reference substances for the quality research of atosiban acetate bulk drugs and atosiban acetate injections to ensure the product quality.

Description

technical field [0001] The invention relates to an impurity of an active polypeptide drug and a preparation method thereof, in particular to a preparation method of an atosiban acetate impurity. Background technique [0002] Atosiban acetate injection was first developed by Ferring AB (Swedish Ferring Company), and was first authorized for marketing by EMEA in 2000. Its trade name is (Yibao), and was approved for marketing in China in 2006, and is mainly used for pregnant women to postpone imminent premature birth. [0003] Atosiban is an oxytocin analogue that exists in the form of acetate in medicines. It is a competitive antagonist of oxytocin receptors in the uterus and on the fetal membranes. It is the only uterine-specific drug for the treatment of premature labor. The uterine tocolytic, its mechanism of action is to compete with oxytocin for the oxytocin receptors on the myometrium and fetal membranes, reduce the efficacy of oxytocin, reduce the level of calcium ion...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/20C07K1/06C07K1/04C07K1/02
CPCC07K7/16
Inventor 吴乾方薄乐蒋名更云晓凌振宏
Owner HAINAN ZHONGHE PHARM CO LTD
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