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Method for preparing eptifibatide and precursor thereof

A technology for eptifibatide and compounds, applied in the field of compound synthesis, can solve the problems of low purification yield, increased purification difficulty, waste of 6-peptide fragments, etc.

Active Publication Date: 2011-09-07
HANGZHOU HUADI GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, this invention causes serious waste of 6 peptide fragments due to steric hindrance when linking mercaptopropionic acid, and has [Mpr-Har-Gly-Gly-Asp-Trp-Pro-Cys] (NH 2 ) produced, resulting in increased difficulty in purification, low purification yield, and the total cost has no obvious advantage over solid-phase synthesis

Method used

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  • Method for preparing eptifibatide and precursor thereof
  • Method for preparing eptifibatide and precursor thereof
  • Method for preparing eptifibatide and precursor thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Embodiment 1: the synthesis of Boc-Asp(OtBu)-Trp-Pro-OH

[0061] In a 50 ml round bottom flask, add Boc-Asp(OtBu)-OSu (1.932g), H-Trp-Pro-NH 2 (1.506g), dissolved with 40 ml of anhydrous DMF, cooled to a constant temperature in an ice-water bath, added DCC (1.030g), stirred at room temperature for 3 hours, and detected that the reaction was complete. The precipitate produced by the reaction was removed by suction filtration, concentrated under reduced pressure to remove DMF, and then dissolved with a large amount of ethyl acetate, and then dissolved with NaHCO 3 Wash, wash with dilute hydrochloric acid, wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry ethyl acetate to obtain a solid.

[0062] HPLC measures the purity of Boc-Asp(OtBu)-Trp-Pro-OH: greater than 93%, target content 2.648g, yield is 92.5%, mass spectrometry detects MS=572 (M + ).

Embodiment 2

[0063] Example 2: Boc-Asp(OtBu)-Trp-Pro-Cys(Npys)-NH 2 Synthesis

[0064] Add Boc-Asp(OtBu)-Trp-Pro-OH (2.362g), H-Cys(Npys)-NH 2 (1.372g), HOSu (0.575g), dissolved with 40 ml of anhydrous DMF, after adding DCC (1.030g) under ice-water bath, stirred at room temperature for 3 hours, and detected that the reaction was complete. The precipitate produced by the reaction was removed by suction filtration, concentrated under reduced pressure to remove DMF, and then dissolved with a large amount of ethyl acetate, and then dissolved with NaHCO 3 Wash, wash with dilute hydrochloric acid, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate to dry ethyl acetate to obtain a solid.

[0065] Determination of Boc-Asp(OtBu)-Trp-Pro-Cys(Npys)-NH by HPLC 2 Purity: greater than 91%, target content 3.823g, yield is 90.5%, mass spectrometry detects MS=845 (M + ).

Embodiment 3

[0066] Example 3: Synthesis of Boc-Har-Gly-Ome

[0067] In a 50 ml round bottom flask, add Boc-Har-OH (1.440g), NH2-Gly-Ome (0.445g), HOSU (0.575g), dissolve with 40 ml of anhydrous DMF, add DCC (1.030 g) under ice-water bath g) After stirring at room temperature for 2 hours, it was detected that the reaction was complete. The precipitate produced by the reaction was removed by suction filtration, concentrated under reduced pressure to remove DMF, and then dissolved with a large amount of ethyl acetate, and then dissolved with NaHCO 3 Wash, wash with dilute hydrochloric acid, wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry ethyl acetate to obtain a solid.

[0068] HPLC measures the Boc-Har-Gly-Ome purity: greater than 94%, target object content 1.670g, yield is 93%, mass spectrometry detects MS=359 (M + ).

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Abstract

The invention discloses a method for synthesizing eptifibatide, which comprises the following steps of: synthesizing the 1-3 fragment and 4-7 fragment of the eptifibatide, coupling the two fragments by using a disulfide bond to obtain the 4-7-1-3 fragment of the eptifibatide, intramolecularly combining to form a cyclic peptide, and removing a protection group to form the eptifibatide. A liquid phase synthesis method is adopted, and a ring is formed through a molecular lactam bond, so the yield of the eptifibatide is higher than that of the eptifibatide through the ring formation of the disulfide bond, total cost is obviously reduced, and expensive resin is avoided.

Description

technical field [0001] The present invention relates to the technical field of compound synthesis, especially the preparation method of eptifibatide, and also relates to the precursor or intermediate of eptifibatide, and the preparation method of these intermediates or precursors. Background technique [0002] Coronary heart disease is the number one cause of death in western developed countries. Millions of people suffer from the disease every year. In my country, there are about 1 to 2 million people every year, and there is a rising trend. Although modern technology can be used for shaping or bypass surgery, but There is a higher chance of getting sick again after surgery, and medication is required. Eptifibatide is a high-efficiency platelet protein IIb / IIIa cyclic heptapeptide antagonist. It is a short-acting parenteral antithrombotic agent for the treatment of unstable angina during percutaneous coronary intervention and as an auxiliary thrombolytic agent for Treatment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/02
CPCY02P20/55
Inventor 谷海涛刘标俞保彬赵呈青
Owner HANGZHOU HUADI GRP CO LTD
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