Liquid-phase synthesis method of eptifibatide

A liquid-phase synthesis, eptifibatide technology, applied in the field of biochemistry, can solve the problems of increased by-products, expensive raw materials, increased patient burden, etc., and achieves the effects of improving yield, reducing product cost, and improving production efficiency

Active Publication Date: 2013-12-18
山东博创生物科技有限公司
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Problems solved by technology

Although this method can effectively synthesize eptifibatide, the raw materials are expensive, and there are many by-products in the synthesis of linear peptides, and the utilization rate of raw materials is low
[0004] The existing liquid phase synthesis method is also reported. Patent CN200,910,101,674 discloses a new full liquid phase synthesis method of eptifibatide, and patent CN200,910,156,804 provides a synthetic liquid phase preparation process of eptifibatide. But the yield of eptifibatide in these liquid phase synthesis methods is low, is not suitable for industrialized production
[0005] Among the currently known synthetic methods, the solid-phase synthesis of eptifibatide is an ideal method for laboratory research. This method is efficient and rapid, but the raw material utilization rate of the solid-phase synthesis method is low, and the reagents and solvents used are expensive. And it is not easy to handle, commonly used solvents such as ethanedithiol and DMF are highly toxic and not suitable for industrial production
In addition, this method uses expensive homoarginine as a starting material, which has poor solubility in organic solvents, resulting in increased by-products and reduced synthesis efficiency.
In addition, in the existing liquid-phase synthesis method, due to the low yield, only small-scale production can only be carried out in a reactor of about 1L
These all lead to the increase of the patient's burden due to the high price of eptifibatide. Therefore, there is an urgent need for a new synthetic method that can be produced on a large scale to reduce the cost of eptifibatide and reduce the price of eptifibatide. , to reduce the financial burden on patients

Method used

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  • Liquid-phase synthesis method of eptifibatide

Examples

Experimental program
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Effect test

Embodiment 1

[0058] Example 1. Fmoc-Pro-Cys(Trt)-NH 2 preparation of

[0059] H-Cys(Trt)-NH 2 (MW362.49, 1.812g, 5mmol) was dissolved in 10ml DCM, and DIEA (MW129.24, 1.1ml, 6mmol) was added under stirring; Fmoc-Pro-OH (MW337.37, 1.687g, 5mmol) and HOCt (MW .157.13, 0.943g, 6.0mmol) was dissolved in 25ml DCM, and DIC (MW126.20, 0.91ml, 6.0mmol) was slowly added dropwise under stirring to the above solution, and reacted for 15min. Then this mixed solution was added dropwise to H-Cys(Trt)-NH 2 / DIEA / DCM mixture, stirred at room temperature for 4 h, and TLC detected that the reaction was complete. The reaction solution was filtered with NaHCO 3 (0.2M, 25ml*2), hydrochloric acid (0.2M, 20ml*2) and saturated brine (30ml) were extracted sequentially, anhydrous Na 2 SO 4 After drying and concentrating under reduced pressure, an oily substance was obtained, and Et 2 O is placed, and a white solid is obtained, which is Fmoc-Pro-Cys(Trt)-NH 2 (MW.681.84), and separated and purified by HPLC (...

Embodiment 2

[0060] Example 2.H-Pro-Cys(Trt)-NH 2 preparation of

[0061] Take Fmoc-Pro-Cys(Trt)-NH 2 (MW681.84, 3.410g, 5mmol) dissolved in 50mlEt 2 In NH / DCM (10%), the reaction was carried out for 6h, and monitored by TLC until the reaction was complete. The reaction solution was decompressed at 30°C to remove DCM and Et 2 NH, the residue was dissolved in DCM and washed with hydrochloric acid (0.1M) until neutral, followed by Na 2 CO 3 (0.1M), water and saturated brine extraction, anhydrous Na 2 SO 4 After drying, concentrate under reduced pressure to obtain H-Pro-Cys(Trt)-NH 2 (MW.460.14), and separated and purified by HPLC (HPLC: 8.79min), product mass spectrometry analysis: MS=462.1[M+].

Embodiment 3

[0062] Example 3.Fmoc-Trp-Pro-Cys(Trt)-NH 2 preparation of

[0063] H-Pro-Cys(Trt)-NH 2 (MW459.60, 2.298g, 5mmol) was dissolved in 15ml DCM, and DIEA (MW129.24, 1.1ml, 6mmol) was added under stirring; Fmoc-Trp-OH (MW426.46, 2.132g, 5mmol) and HOCt (MW .157.13, 0.943g, 6.0mmol) was dissolved in 30ml DCM, and DIC (MW126.20, 0.91ml, 6.0mmol) was slowly added dropwise under stirring to the above solution, and reacted for 15min. Then this mixed solution was added dropwise to H-Pro-Cys(Trt)-NH 2 / DIEA / DCM mixture, stirred at room temperature for 6 h, and TLC detected that the reaction was complete. The reaction solution was filtered with NaHCO 3 (0.2M, 25ml*2), hydrochloric acid (0.2M, 20ml*2) and saturated brine (30ml) were extracted sequentially, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to get an oil, add DCM / Et 2 O crystallized to obtain white solid Fmoc-Trp-Pro-Cys(Trt)-NH 2 (MW.868.05), and separated and purified by HPLC (HPLC: 11.63min), product m...

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Abstract

The invention relates to a liquid-phase synthesis method of eptifibatide as a polypeptide medicament and belongs to the technical field of synthesis of polypeptides. According to the technical scheme, the liquid-phase synthesis method comprises the following steps: (1) synthesizing a peptide fragment Mpa(R1)-Lys(R2)-Gly-OH; (2) synthesizing a peptide fragment H-Asp(R3)-Trp-Pro-Cys(R4)-NH2; (3) condensing the peptide fragment Mpa(R1)-Lys(R2)-Gly-OH and the peptide fragment H-Asp(R3)-Trp-Pro-Cys(R4)-NH2 to obtain a linear peptide Mpa(R1)-Lys(R2)-Gly-Asp(R3)-Trp-Pro-Cys(R4)-NH2; (4) cyclizing the linear peptide Mpa(R1)-Lys(R2)-Gly-Asp(R3)-Trp-Pr-Cys(R4)-NH2 to form an intramolecular disulfide bond to obtain a side chain protected cyclopeptide; (5) removing a side chain protecting group of the cyclopeptide; and (6) converting a side chain amino group of the cyclopeptide Lys into a guanidine group to obtain the eptifibatide. According to the liquid-phase synthesis method of the eptifibatide, an initiating raw material, namely an Fmoc-Har-OH special amino acid derivative is avoided, a condition and method for converting the amino group of the cyclopeptide into the guanidine group are established, and a raw material reagent is low in cost and easily obtained, so that the product cost is effectively reduced and the production benefit is remarkably increased.

Description

technical field [0001] The invention relates to a liquid-phase synthesis method of eptifibatide, which belongs to the field of biochemistry. Background technique [0002] Eptifibatide was developed by COR Therapeutic Company of the United States and launched in the United States in 1998 for the treatment of acute coronary syndrome. By inhibiting coagulation factor I, it binds to platelet glycoprotein IIb / IIIa receptors, thereby inhibiting platelet aggregation. In clinical application, it has shown good curative effect on the treatment of cardiovascular diseases such as unstable angina, acute myocardial infarction, and coronary intervention. At present, cardiovascular diseases are increasing year by year and have become one of the common diseases that pose a serious threat to human health in modern society. As a polypeptide cardiovascular system drug, eptifibatide has the advantages of high efficacy and low side effects, and has been widely used in clinical practice. applic...

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 高秀伟高秀岩任孝敏王朴
Owner 山东博创生物科技有限公司
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