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Preparation method of anticoagulant polypeptide

A crude peptide and peptide resin technology, applied in the field of medicinal chemistry, can solve the problems of high cost, many purification steps, and unsatisfactory results, and achieve the effects of low cost, simple operation, and considerable economic and practical value

Inactive Publication Date: 2012-10-03
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent 201110144317.9 discloses a two-step purification plus one-step salt conversion HPLC purification method, but this method has many purification steps and high cost; the preparation method of bivalirudin reported in US20070093423 is purified by HPLC to obtain the purity of bivalirudin refined peptide Only greater than 98.5%, Asp9-Bivalirudin is only less than 0.5%, the results are not satisfactory
Therefore, the purification of bivalirudin is a difficult point in the preparation process, especially the large-scale preparation and purification of kilograms or more has become one of the bottlenecks restricting the industrialization of bivalirudin

Method used

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  • Preparation method of anticoagulant polypeptide
  • Preparation method of anticoagulant polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of Fmoc-Gly-Gly-CTC Resin with a degree of substitution of 0.6mmol / g

[0042] Weigh 300g of 2-CTC resin with a substitution degree of 1.0mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, take 79.65g of Fmoc-Gly-Gly-OH and wash it with DMF Dissolved, activated by adding 97.8mL DIPEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, reacted for 2 hours, added 243mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Gly-Gly-CTC resin, and the detected substitution degree is 0.628mmol / g.

Embodiment 2

[0043] Example 2: Preparation of Fmoc-Gly-Gly-CTC Resin with a degree of substitution of 1.0mmol / g

[0044] Weigh 300g of 2-CTC resin with a substitution degree of 1.2mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 159.3g of Fmoc-Gly-Gly-OH and wash it with DMF Dissolved, activated by adding 195.6mL DIPEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, and reacted for 2 hours, then added 243mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Gly-Gly-CTC resin, and the detected substitution degree is 0.988mmol / g.

Embodiment 3

[0045] Example 3: Preparation of Fmoc-Gly-Gly-CTC Resin with a degree of substitution of 0.8mmol / g

[0046] Weigh 300g of 2-CTC resin with a substitution degree of 1.0mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, take 106.2g of Fmoc-Gly-Gly-OH and wash it with DMF Dissolved, activated by adding 130.4mL DIPEA in an ice-water bath, then added to the above-mentioned reaction column filled with resin, reacted for 2 hours, added 243mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Gly-Gly-CTC resin, the detection degree of substitution is 0.806mmol / g.

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Abstract

The invention relates to a preparation method of an anticoagulant polypeptide and discloses a preparation method of bivalirudin, and belongs to the technical field of pharmaceutical chemistry. The preparation method comprises the following steps: purifying a bivalirudin crude peptide by a reverse phase / weak cation exchange mixed-mode HPLC (high performance liquid chromatography) method; transferring a salt by a reverse phase HPLC method; and collecting and lyophilizing a solution to obtain the bivalirudin. The preparation method is easy to operate, low in cost and high in gram yield of the bivalirudin and is applicable for large-scale industrial production of the bivalirudin; by virtue of hydrophobicity and chargeability difference, impurities in the crude peptide can be separated and removed well at one time; and the prepared bivalirudin is high in purity and low in impurity content and has a considerable economic value and a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a preparation method of an anticoagulant polypeptide, in particular to a preparation method of bivalirudin. Background technique [0002] Bivalirudin (Angiomax) is a synthetic anticoagulant drug. Its anticoagulant component is a peptide with 20 amino acid residues at the C-terminus of a hirudin derivative, and its structural sequence is D-Phe-Pro-Arg-Pro-Gly- Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH. Bivalirudin is a potent direct thrombin inhibitor that directly inhibits thrombin by binding to the catalyst site and the anion export site of the circulation and thrombin clot. Early clinical studies have shown that bivalirudin anticoagulant therapy is effective and has a lower incidence of bleeding events. Compared with traditional heparin anticoagulant therapy, it is safer to use and is a thrombin inhibitor that has been widely used clinically in r...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/36C07K1/20C07K1/18
Inventor 宓鹏程覃亮政马亚平袁建成
Owner HYBIO PHARMA
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