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Eptifibatide synthesis method

A technology of eptifibatide and a synthesis method, which is applied in the field of eptifibatide synthesis, can solve the problems of affecting the purity of crude products, the reaction is not easy to be completed, and the purification difficulty is increased, and achieves shortening time, shortening production cycle, and cyclization reaction. quick effect

Inactive Publication Date: 2016-05-18
何润泽
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are also two shortcomings in the Boc strategy solid-phase method (that is: tert-butoxycarbonyl strategy solid-phase method) in the prior art: 1, in the process of converting arginine into homoarginine, it is under heterogeneous conditions carried out, the reaction is not easy to complete
Whether this degree of conversion is complete cannot be detected and tracked on the resin, thus affecting the purity of the crude product, resulting in increased difficulty in purification and reduced yield
2. When the polypeptide is washed off from the resin, highly corrosive and highly toxic hydrogen fluoride is used, which is easy to cause environmental pollution and cause a series of environmental and social problems

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0040] 1. Prepare Fmoc-Cys(Trt)-Linker-AM resin: wash 80mL Fmoc-Linker-AM resin with 10mLDMF twice (5mLDMF / time); then soak in 10-15mL dichloromethane for about 10 minutes to fully swell the resin , add 10-15mL of piperidine and DMF with a volume ratio of 1:4, heat in a water bath or oil bath or microwave, react at 60°C to 80°C for 2 minutes, drain, wash with 15mLDMF three times (5mLDMF / time) , add 10-15mL of the mixture of Fmoc-Cys(Trt)-OH, Oxyma and DIC dissolved in DMF, heat in a water bath, oil bath or microwave, react at 60°C to 80°C for about 15 minutes, drain, and then Washed three times with 15mLDMF (5mLDMF / time), the Fmoc-Cys(Trt)-Linker-AM resin was obtained.

[0041] Please note: Oxyma can also be replaced by HOBt. The amount of amino acid (such as Fmoc-Cys(Trt)–OH) and condensation reagent (such as Oxyma and DIC) used is twice or more than the mole of resin, and the following process is the same.

[0042] 2. To prepare Fmoc-Pro-Cys(Trt)-Linker-AM resin, after the ...

Embodiment 2

[0051] 1. Preparation of Fmoc-Cys(Trt)-Linker-AM resin: wash 60mL of Fmoc-Linker-AM resin with 12mLDMF twice (4mLDMF / time); then soak in 10mL of dichloromethane for about 10 minutes to fully swell the resin, add 15mL of piperidine and DMF with a volume ratio of 1:4, heated by microwave, reacted at 60-80°C for 2 minutes, drained, washed three times with 12mL of DMF (4mLDMF / time), added Fmoc-Cys dissolved in DMF (Trt)-OH, Oxyma and DIC mixture 15mL, heated by microwave, reacted at 60-80 ℃ for 15 minutes, sucked dry, and then washed three times with 12mLDMF (4mLDMF / time), Fmoc-Cys(Trt )-Linker-AM resin.

[0052] Please note: Oxyma can also be replaced by HOBt, the amount of amino acid (such as Fmoc-Cys(Trt)–OH) and condensation reagent (such as Oxyma and DIC) used is twice the mole of resin, the following process is the same.

[0053] 2. To prepare Fmoc-Pro-Cys(Trt)-Linker-AM resin, after the above steps, add 15mL of piperidine and DMF with a volume ratio of 1:4, heat with micro...

Embodiment 3

[0062] 1. Preparation of Fmoc-Cys(Trt)-Linker-AM resin: wash 60mL of Fmoc-Linker-AM resin with 9mLDMF twice (3mLDMF / time); then soak in 15mL of dichloromethane for about 10 minutes to fully swell the resin, add 10 mL of piperidine and DMF with a volume ratio of 1:3, heated in a water bath, reacted at 70°C for 3 minutes, drained, washed three times with 9 mL of DMF (3 mL of DMF each time), added Fmoc-Cys (Trt )-OH, Oxyma and DIC mixture 12mL, heated in a water bath, reacted at 70°C for 18 minutes, sucked dry, and then washed three times with 12mLDMF (4mLDMF / time) to obtain Fmoc-Cys(Trt)-Linker- AM resin.

[0063] Please note: Oxyma can also be replaced by HOBt, the amount of amino acid (such as Fmoc-Cys(Trt)–OH) and condensation reagent (such as Oxyma and DIC) used is twice the mole of resin, the following process is the same.

[0064] 2. To prepare Fmoc-Pro-Cys(Trt)-Linker-AM resin, after the above steps, add 10mL of piperidine and DMF with a volume ratio of 1:3, heat in a wa...

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Abstract

The invention discloses an eptifibatide synthesis method. Fluorenylmethoxycarbonyl aminomethyl resin is used as a carrier, the method comprises amino acid condensation reactions from Step 1 to Step 7, resin connected with 7 amino acids is cut and linear thiohydracrylic acid-homoarginine-glycine-aspartic acid-tryptophan-proline-cysteine-NH2 is obtained in Step 8, a ring is formed under the catalysis of 2,2'-dipyridyl disulfide in Step 9, and eptifibatide is obtained. Further, the condensation reactions and deprotection reactions are conducted at 60-80 DEG C. The method has the characteristics of high yield, few byproduct and simplicity in separation and purification, and compared with the prior art, the method has the advantages that a lot of time is saved and the method is applicable to pilot production and industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing polypeptides, in particular to a method for synthesizing eptifibatide. Background technique [0002] Eptifibatide, the English name is Eptifibatide, the molecular formula is C 35 h 49 N 11 o 9 S 2 , the sequence is: Mpr-Har-Gly-Asp-Trp-Pro-Cys-NH 2 , Eptifibatide is clinically a specific GPIIb / IIIa receptor antagonist that can be injected intravenously. It is a colorless, amorphous, amorphous white powder, easily soluble in water. By preventing fibrin from binding to GPIIb / IIIa receptors, thereby inhibiting platelet aggregation and preventing thrombosis, this product is clinically used as an adjuvant drug for heparin or aspirin. [0003] Eptifibatide is a synthetic cyclic heptapeptide, which is a platelet glycoprotein GPIIb / IIIa receptor antagonist, which can block the platelet aggregation reaction caused by various activators, and is the strongest specific platelet aggregation inhibitor known ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCC07K7/06
Inventor 何润泽
Owner 何润泽
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