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Preparation method of bivalirudin

A bivalirudin and coupling technology, which is applied in the field of preparation of bivalirudin, can solve problems such as harsh conditions, difficulty in purification, long peptide sequence, etc., achieve large-scale preparation, increase yield and purity, and condition mild effect

Inactive Publication Date: 2013-02-13
HYBIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Some of the current synthetic methods use liquid phase synthesis, but because the structure of bivalirudin belongs to polypeptide analogs, the peptide sequence is long, the liquid phase reaction is more cumbersome, it is not easy to purify, it takes a long time to synthesize, and the yield is low; in addition, Although the above-mentioned part of patents uses solid-phase synthesis of bivalirudin, the structure of bivalirudin contains a -Gly-Gly-Gly-Gly fragment. In the process of sequentially coupling -Gly, due to the characteristics of Gly itself, it is very easy to be in the Impurities of Bivalirudin±1Gly and Bivalirudin±2Gly are produced before and after the main peak. These impurities are difficult to remove in the subsequent separation, and some patented solid-phase synthesis uses HF for cracking, which requires high equipment performance and harsh conditions, which is not conducive to industrial production.

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  • Preparation method of bivalirudin

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preparation example Construction

[0031] The invention discloses a preparation method of bivalirudin, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0032] PAM Resin, HMPA-AM Resin, HMPA-MBHA Resin, Wang Resin and 2-CTC resins were purchased from Tianjin Nankai Hecheng Co., Ltd., various protected amino acids were purchased from Suzhou Tianma Co., Lt...

Embodiment 1

[0051] Example 1: Preparation of Fmoc-Gly-CTC Resin with a degree of substitution of 0.5mmol / g

[0052] Weigh 150g (0.15mmol) 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 66.9g (0.225mmol) of Fmoc -Gly-OH was dissolved in DMF, activated by adding 58.2g (0.45mmol) DIPEA in an ice-water bath, and then added to the above-mentioned reaction column filled with resin. After 2 hours of reaction, 182mL of anhydrous methanol was added to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Gly-CTC resin, the detection degree of substitution is 0.511mmol / g.

Embodiment 2

[0053] Embodiment 2: the preparation of the Fmoc-Gly-CTC Resin that substitution degree is 1.0mmol / g

[0054] Weigh 150g (180mmol) 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, take 107.1g (360mmol) of Fmoc-Gly -OH was dissolved in DMF, activated by adding 69.8g (540mmol) DIPEA in an ice-water bath, and then added to the above-mentioned reaction column equipped with resin. After 2 hours of reaction, 182mL of anhydrous methanol was added to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Gly-CTC resin, and the detected substitution degree is 0.986mmol / g.

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Abstract

The invention relates to the field of polypeptide synthesis, and particularly relates to a preparation method of bivalirudin. In the method, a polypeptide segment Fmoc-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-OH obtained through solid phase synthesis is used as a raw material, thus avoiding the problems of bivalirudin+ / -1Gly and bivalirudin+ / -2Gly. Besides, by using a specific coupling reagent, the content of the isomer L-Phe is greatly reduced; and meanwhile, the yield and purity of the product are enhanced, the operation process is convenient, and the conditions are mild, thereby being beneficial to large-scale preparation.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a preparation method of bivalirudin. Background technique [0002] Bivalirudin, the amino acid sequence is shown in SEQ ID No.3, that is, D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu- Ile-Pro-Glu-Glu-Tyr-Leu-OH is a thrombin inhibitor used clinically. Early clinical studies have shown that bivalirudin anticoagulant therapy is effective and has a lower incidence of bleeding events, compared with traditional It is safer to use heparin anticoagulant therapy. Bivalirudin directly inhibits the action of thrombin by binding to the catalyst site and the anion export site of the circulation and thrombin clot. [0003] There are a large number of reports at home and abroad about the preparation method of bivalirudin. Chinese patent CN101475631B reports the synthesis of bivalirudin by a full liquid phase method. First, three fully protected fragments containing 6, 6, a...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/04
Inventor 朱日成宓鹏程刘建马亚平袁建成
Owner HYBIO PHARMA
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