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Preparation method for eptifibatide anticoagulant drug

A technology of anticoagulant and eptifibatide, which is applied in the field of preparation of anticoagulant drugs of eptifibatide, can solve the problems that the product purity is difficult to meet the ideal requirements, adverse drug reactions, and many synthesis steps, etc., so as to achieve easy removal and easy operation The effect of simplicity and low process cost

Inactive Publication Date: 2019-02-05
重庆科脉生物化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the present existing methods generally have many synthetic steps, complicated processes, and the shortcomings of being difficult to industrialize, especially the product purity is difficult to meet the ideal requirements, and the purity is high, which is easy to cause adverse drug reactions. Synthetic process is of great significance

Method used

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  • Preparation method for eptifibatide anticoagulant drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Preparation of PNZ-Lys(Boc)-Gly-OBu-t

[0021] Add H-Gly-OBu-t (131g, 1mol) into the reaction flask, dissolve in 500mL of dichloromethane, and slowly add 220mL of DIEA (1.2mol) under ice cooling; the peptide condensation agent A (470g, 1.0mol ) and PNZ-Lys(Boc)-OH (425g, 1mol) were dissolved in 1000mL of dichloromethane, activated at 0°C for 10 minutes, and then slowly added dropwise to the above-mentioned H-Gly-OBu-t in dichloromethane solution , stirred at 0° C. for 30 minutes, and the reaction was monitored by TLC to complete. After the reaction solution was filtered, washed with aqueous sodium bicarbonate solution, aqueous hydrochloric acid and distilled water, the organic phase of dichloromethane was dried over anhydrous sodium sulfate, concentrated under reduced pressure, refined with ethyl acetate and chloroform to obtain a white solid PNZ-Lys(Boc)- Gly-OBu-t, yield 97.8%, purity 98.9%, MS[M+1] + 539.

Embodiment 2

[0023] Preparation of H-Lys(Boc)-Gly-OBu-t

[0024] Dissolve PNZ-Lys(Boc)-Gly-OBu-t (538g, 1mol) in 1000mL methanol, then add palladium carbon (5wt% palladium, 24g) / hydrogen, react at room temperature, filter after the reaction, and concentrate to a system of 200mL, cooled at 0°C and filtered to obtain solid H-Lys(Boc)-Gly-OBu-t, the yield was 98.8%, the purity was 98.7%, MS[M+1] + 360.

Embodiment 3

[0026] Preparation of H-Lys(Boc)-Gly-OBu-t

[0027] Dissolve PNZ-Lys(Boc)-Gly-OBu-t (538g, 1mol) in 1000mL methanol, then add platinum carbon (5wt% palladium, 24g) / hydrogen, react at room temperature, filter after the reaction, and concentrate to a system of 200mL, cooled at 0°C and filtered to obtain solid H-Lys(Boc)-Gly-OBu-t, the yield was 98.0%, the purity was 98.0%, MS[M+1] + 360.

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Abstract

The invention discloses a preparation method for an eptifibatide anticoagulant drug and belongs to the technical field of synthesis of drug intermediates. The invention is characterized in that by utilizing a polypeptide condensing agent A, step 1, a tripeptide fragment Mpa (Trt)-Lys (Boc)-Gly-OH is synthesized firstly; step 2, a tetrapeptide fragment H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2 is synthesized; and step 3, a disulfide bond is formed firstly to form a linear peptide, then condensation is performed to form cyclopeptide, and a guanidine group is formed finally to prepare eptifibatide as atarget product. The technology is high in yield as well as simple and convenient to treat; and the prepared eptifibatide is high in purity of raw materials and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of eptifibatide anticoagulant medicine. Background technique [0002] Eptifibatide (structure as shown in formula I), also known as Eptifibatide (Eptifibatide), eptifibatide, its structure can be split into seven components: L-cysteine ​​(Cys), L-proline amino acid (Pro), L-tryptophan (Trp), L-aspartic acid (Asp), glycine (Gly), L-homoarginine (Harg), β-mercaptopropionic acid (Mpr), yes An antiplatelet aggregation agent. Eptifibatide was launched in the United States in 1998 as an anti-platelet aggregation drug for the treatment of acute coronary syndrome, and its clinical application is becoming more and more extensive. [0003] [0004] Currently, there are many synthetic methods reported in Eptifibatide patents, mainly including liquid phase synthesis and solid phase synthesis (CN106554389 A, CN 105218641 A, CN 105001304 A, CN 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/02A61P7/02
CPCA61P7/02C07K7/06
Inventor 崔振伟张玮玮过治军
Owner 重庆科脉生物化工有限公司
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