Preparation method for eptifibatide

A technology for eptifibatide and peptide fragments, which is applied in the field of polypeptide drug preparation, can solve the problems of reducing the purification time and generating cost, prolonging the generating time, and low water-phase concentration efficiency, etc., so as to shorten the production process steps, reduce the purification difficulty, and achieve a wide range of The effect of practical value and application prospect

Active Publication Date: 2015-11-11
SICHUAN JISHENG BIOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In the above two patent documents of the prior art, the crude product needs to be concentrated before purification, thereby reducing the purification time and reducing the production cost. In the prior art, the crude product is placed in the water phase for cyclization and oxidation, because the water phase The efficiency of concentration is low, and it cannot be concentrated at high temperature, and the method of the prior art will greatly prolong the generation time

Method used

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  • Preparation method for eptifibatide
  • Preparation method for eptifibatide
  • Preparation method for eptifibatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The preparation of step 1Fmoc-Pro-Cys (Trt) resin

[0054] Add Fmoc-Cys(Trt) carrier resin (0.45mmol / g, 50mmol) into the reactor, wash once with DMF, and swell with DCM for 30 minutes. After swelling, 20% PIP / DMF solution was used to deprotect Fmoc for 2 times. After deprotection was detected, DMF was washed 3 times, and DCM was washed 3 times. 50.6g Fmoc-Pro-OH, (150mmol), 20.3gHOBt (150mmol), 19gDIC were dissolved in DMF, added to a solid-phase reactor, and reacted at room temperature for 3h (the end point of the reaction was determined by the ninhydrin method), and the reaction was completed. Wash 3 times with DMF and 3 times with DCM.

[0055] Preparation of step 2Fomc-Trp(boc)-Pro-Cys(Trt) resin

[0056] In the Fmoc-Pro-Cys (Trt) resin in step 1, 20% PIP / DMF solution was used to deprotect Fmoc twice, and after the deprotection was detected, wash three times with DMF and three times with DCM. Dissolve 78.9gFmoc-Trp(boc)-OH(150mmol), 20.3gHOBt(150mmol), and 19gDIC...

Embodiment 2

[0071] The preparation of step 1Fmoc-Pro-Cys (Trt) resin

[0072] Add Fmoc-Cys(Trt) carrier resin (0.45mmol / g, 50mmol) into the reactor, wash once with DMF, and swell with DCM for 30 minutes. After swelling, 20% PIP / DMF solution was used to deprotect Fmoc for 2 times. After deprotection was detected, DMF was washed 3 times, and DCM was washed 3 times. 50.6g Fmoc-Pro-OH, (150mmol), 20.3gHOBt (150mmol), 19gDIC were dissolved in DMF, added to a solid-phase reactor, and reacted at room temperature for 3h (the end point of the reaction was determined by the ninhydrin method), and the reaction was completed. Wash 3 times with DMF and 3 times with DCM.

[0073] Preparation of step 2Fomc-Trp(boc)-Pro-Cys(Trt) resin

[0074] In the Fmoc-Pro-Cys (Trt) resin in step 1, 20% PIP / DMF solution was used to deprotect Fmoc twice, and after the deprotection was detected, wash three times with DMF and three times with DCM. Dissolve 78.9gFmoc-Trp(boc)-OH(150mmol), 20.3gHOBt(150mmol), and 19gDIC...

Embodiment 3

[0089] The preparation of step 1Fmoc-Pro-Cys (Trt) resin

[0090] Add Fmoc-Cys(Trt) carrier resin (0.45mmol / g, 50mmol) into the reactor, wash once with DMF, and swell with DCM for 30 minutes. After swelling, 20% PIP / DMF solution was used to deprotect Fmoc for 2 times. After deprotection was detected, DMF was washed 3 times, and DCM was washed 3 times. 50.6g Fmoc-Pro-OH, (150mmol), 20.3gHOBt (150mmol), 19gDIC, 0.5g triethylamine and 0.45g N-ethyl p-toluidine were dissolved in DMF, added to a solid-phase reactor, and reacted at room temperature for 3h ( The end point of the reaction is determined by the ninhydrin method), and the reaction is completed, washed 3 times with DMF and 3 times with DCM.

[0091] Preparation of step 2Fomc-Trp(boc)-Pro-Cys(Trt) resin

[0092] In the Fmoc-Pro-Cys (Trt) resin in step 1, 20% PIP / DMF solution was used to deprotect Fmoc twice, and after the deprotection was detected, wash three times with DMF and three times with DCM. Dissolve 78.9gFmoc-T...

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Abstract

The invention discloses a preparation method for eptifibatide. The method includes the steps of sequentially coupling and connecting Fmoc-protected amino acid and a protected amino acid tripeptide section with Fmoc-Cys(Trt) resin as a coupling resin carrier, splitting eptifibatide resin through a split agent, oxidizing reduced type eptifibatide in an acetonitrile aqueous solution, conducting condensation after oxidation, and conducting purification, salt transfer and freeze drying on crude eptifibatide product concentrated liquor to obtain a fine eptifibatide product. By means of the preparation method, production cost can be effectively reduced, yield is increased, and the content of impurities in the finished product is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of polypeptide drugs, in particular to a preparation method of eptifibatide. Background technique [0002] Eptifibatide, alias Eptifibatide, Eptifibatide, Eptifibatide, English name Eptifibatide. [0003] The structural formula of eptifibatide is as formula I: [0004] [0005] The molecular formula is: C35H49N11O9S2 [0006] Eptifibatide is a synthetic cyclic peptide containing one mercaptopropionic acid and six amino acid residues. It is a specific and targeted platelet glycoprotein GPIIb / IIIa receptor antagonist, which selectively and reversibly inhibits the final common pathway of platelet aggregation (plasma coagulation due to the combination of coagulation factor Ⅰ and GPⅡb / Ⅲa), and can reverse the cause of thrombosis resulting in an ischemic state. Eptifibatide is mainly used clinically to treat unstable angina pectoris and acute myocardial infarction. Its main adverse reaction i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
Inventor 龙春艳胡阳
Owner SICHUAN JISHENG BIOPHARM CO LTD
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