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Method for synthesizing eptifibatide

A technology of eptifibatide and synthesis method, which is applied in the preparation method of peptide, chemical equipment and method, peptide, etc., and can solve the problems of complex steps, many by-products of production, and difficulty in stability

Inactive Publication Date: 2010-06-30
SHANGHAI AMBIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although these synthetic methods have a large production capacity, they consume a long time and have complicated steps. There are many control items in GMP production, which are not easy to be stable, and there are many by-products produced. The removal of impurities requires repeated washing or other means of purification, making the existing process Yield is 25-30%, resulting in high cost; and impurities can only be controlled in the range of 0.3-0.5%

Method used

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  • Method for synthesizing eptifibatide
  • Method for synthesizing eptifibatide
  • Method for synthesizing eptifibatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Synthesis of Fmoe Rink amide AM resin (Fmoc-polypeptide resin)

[0101] The following substances Fmoc Rink linker / TBTU / HOBt / NMM (molar ratio 2.0:1.9:4) were condensed with AM resin (substitution degree range 0.8-1.0mmol / g), and stirred at room temperature for 3 hours.

[0102] The resin is used after washing and drying.

[0103] Fmoc deprotection

[0104] The Fmoc was removed by using 10% piperidine / 3% HOBT / 1% DBU / DMF solution, and the deprotection was performed twice consecutively, and the time was 10 min and 20 min respectively. Drain the deprotection solution and wash with DMF and methanol respectively. After exhaustion, Kaiser test was used to evaluate the removal of Fmoc.

[0105] Fmoc amino acid condensation steps:

[0106] The reactor was charged with Fmoc-AA-OH / HOBt (3 equiv / 3 equiv to Fmoc-Rink amide AM resin) / DMF solution followed by DIC (3 equiv to Fmoc-Rink amide AM resin). During the reaction for three hours, it was monitored by Kaiser test.

[0107] ...

Embodiment 2

[0123] Synthesis of Fmoc-Rink amide AM resin

[0124] The following substances Fmoc Rink linker / TBTU / HOBt / NMM (molar ratio 2.0:1.9:4) were condensed with AM resin (substitution degree range 0.8-1.0mmol / g), and stirred at room temperature for 3 hours.

[0125] and Ac20 / Pyridine / DMF (60v: 50v: 500v) capped to obtain. Drain the reaction solution thoroughly and wash 6 times. The resin is used after washing and drying.

[0126] Fmoc deprotection

[0127] The Fmoc was removed by using 20% ​​piperidine / 1% HOBT / 0% DBU / DMF solution, and the deprotection was performed twice consecutively, and the time was 10 min and 20 min respectively. Drain the deprotection solution and wash with DMF and methanol respectively. After exhaustion, Kaiser test was used to evaluate the removal of Fmoc.

[0128] Fmoc amino acid condensation steps:

[0129] The reactor was charged with Fmoc-AA-OH / HOBt (1 equiv / 1 equiv to Fmoc-Rink amide AM resin) / DMF solution followed by DIC (1.5 equiv to Fmoc-Rink ami...

Embodiment 3

[0146] Synthesis of Fmoc-Rink amide AM resin

[0147] The following substances Fmoc Rink linker / TBTU / HOBt / NMM (molar ratio 2.0:1.9:4) were condensed with AM resin (substitution degree range 0.8-1.0mmol / g), and stirred at room temperature for 3 hours.

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Abstract

The invention provides a method for synthesizing eptifibatide. The method comprises the steps of: (1) condensing Fmoc Rinklinker with AM resin having a degree of substitution of 0.8 to 1.2 mmol / g, so as to acquire a Fmoc-polypeptide resin, (2) mixing the Fmoc-polypeptide resin with a protective agent and removing the Fmoc protecting base so as to acquire a protected polypeptide resin, (3) condensing the protected amino acid of the Fmoc with the protected polypeptide resin by using the condensing agent, (4) repeating the step (2) to step (3) so as to acquire a hexapeptide resin, (5) condensing the hexapeptide resin with Mpa(Trt)-OH so as to acquire a heptamer resin, (6) separating the heptamer from the resin by using cutting agent so as to acquire the crude product of eptifibatide, and (7) oxidizing and cyclizing the crude product of eptifibatide in order to acquire the eptifibatide. The method of the invention can promote the yield of the eptifibatide, decrease the cost and promote the purity.

Description

technical field [0001] The invention relates to a method for synthesizing Eptifibatide. Background technique [0002] Eptifibatide is a synthetic cyclic heptapeptide containing platelet membrane GP II b / III. The Lys-Glu-Asn sequence (similar to fibrinogen) specifically recognized by the receptor inhibits the binding of platelet membrane GP II b / IIIa receptors to fibrinogen. It can be used to treat patients with myocardial infarction without Q wave, and also to prevent the occurrence of ischemic complications after PT-CA (angioplasty). This medicine is available in oral and injectable formulations. After 5 minutes of intravenous administration, the plasma concentration reaches the peak value. After 4 to 6 hours of administration, the plasma concentration reaches a stable value. When its intravenous injection is at 90-250ug.kg-1, the peak plasma concentration is positively correlated with the dose. The plasma concentration of eptifibatide is positively correlated with its...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCY02P20/55
Inventor 白俊才刘亚东张国庆贾军
Owner SHANGHAI AMBIOPHARM
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