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Method for preparing bivalirudin through solid-liquid combination

A technology for bivalirudin and solution is applied in the field of preparing bivalirudin by solid-liquid combination, and achieves the effects of reducing the difficulty of purification, simple process operation, and being beneficial to industrial large-scale production.

Active Publication Date: 2014-09-10
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to solve the difficulties encountered in the synthesis of bivalirudin above, the present invention provides a method for preparing bivalirudin by solid-liquid combination, which can avoid the production of impurities Bivalirudin ± 1Gly and Bivalirudin ± 2Gly, and can solve the problem of 3-position Arg Coupling is difficult and multiple re-injections are required; at the same time, the purity of the crude peptide is improved, the difficulty of purification is reduced, and the production cost is further reduced, which is conducive to large-scale industrial production of bivalirudin

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Preparation of Boc-Pro-Gly-Gly-OH

[0055] Accurately weigh 79.8g (0.6mol) of Gly-Gly-OH and 127.2g (1.2mol) of sodium carbonate and dissolve in 1200mL of water, slowly add Boc-Pro-OSu THF solution at low temperature (2-8°C) ( 123.6g, 0.6mol) / 1000ml, stirred and reacted, TLC monitored the end point of the reaction, after the reaction was complete, the THF was evaporated off, and 10% citric acid aqueous solution was added under the ice-water bath to adjust the pH value of the solution to 2-3, 1000ml ethyl acetate extracted 3 Once, the organic phases were combined, concentrated by rotary evaporation to 1000ml, washed 3 times with 200ml saturated brine, dried over anhydrous sodium sulfate, crystallized by adding 2000ml of petroleum ether to obtain 148.4g of Boc-Pro-Gly-Gly-OH, with a yield of 75.2%.

Embodiment 2

[0056] Example 2: Preparation of Boc-Pro-Gly-Gly-OH

[0057] Accurately weigh 79.8g (0.6mol) of diglycine peptide Gly-Gly-OH and 63.6g (0.6mol) of sodium carbonate and dissolve it in 1200mL water, slowly add Boc-Pro-OSu THF solution at low temperature (2-8°C) ( 123.6g, 0.6mol) / 1000ml, stirred and reacted, TLC monitored the end point of the reaction, after the reaction was complete, the THF was evaporated off, and 10% citric acid aqueous solution was added under the ice-water bath to adjust the pH value of the solution to 2-3, 1000ml ethyl acetate extracted 3 Once, the organic phases were combined, concentrated by rotary evaporation to 1000ml, washed 3 times with 200ml saturated brine, dried over anhydrous sodium sulfate, crystallized by adding 2000ml of petroleum ether to obtain 145.2g of Boc-Pro-Gly-Gly-OH, with a yield of 73.5%.

Embodiment 3

[0058] Example 3: Preparation of Boc-Pro-Gly-Gly-Gly-Gly-OH

[0059] Accurately weigh 53.2g (0.4mol) of Gly-Gly-OH and 84.8g (0.8mol) of sodium carbonate and dissolve in 800mL of water, slowly add Boc-Pro-Gly-Gly-OSu at low temperature (2-8°C) THF solution (170.4g, 0.4mol) / 1000ml, stirred and reacted, TLC monitored the reaction end point, after the reaction was complete, the THF was evaporated off, and 10% citric acid aqueous solution was added under the ice-water bath to adjust the pH value of the solution to 2~3, 1000ml acetic acid Extract with ethyl ester 3 times, combine the organic phases, concentrate to 800ml by rotary evaporation, wash 3 times with 120ml saturated brine, dry over anhydrous sodium sulfate, add petroleum ether 1200ml for crystallization, and get Boc-Pro-Gly-Gly-Gly-Gly-Gly-OH 128.6g, yield 72.6%.

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Abstract

The invention belongs to the field of polypeptide synthesis and relates to a method for preparing bivalirudin through solid-liquid combination. The bivalirudin is prepared by adopting a method for combining a liquid phase and a solid phase, impurity peptides can be well avoided, the purity of crude peptides is improved, and the production cost is reduced. The method comprises the following steps: synthesizing a fragmental hexapeptide Fmoc-Arg(pbf)-Pro-Gly-Gly-Gly-Gly-OH by adopting a liquid phase method, and connecting peptides onto the solid phase. By utilizing the method, impurity peptides Biv+ / -Gly and Biv+ / -2Gly can be avoided, and the problem that the peptides are difficultly completely coupled during solid phase Arg connection is avoided. By utilizing the synthesis process, the purity of the crude peptides can be over 90 percent, and the purification difficulty is reduced, so that the purity of the final product exceeds 99.5 percent, and the production cost is further reduced. Compared with the prior art, the method disclosed by the invention is simple in operation and low in synthesis cost, and is conductive to large-scale industrial production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing bivalirudin by solid-liquid combination. technical background [0002] Bivalirudin (Bivalirudin), trade name Angiomax, was applied by the U.S. Medicines Company, and was first listed in the U.S. in December 2000 with FDA approval. As an anticoagulant for the treatment of patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Bivalirudin is a hirudin analog, designed and chemically synthesized according to the sequence of hirudin protein. Compared with hirudin, it has the advantages of directness, specificity and reversibility as a thrombin inhibitor. [0003] Bivalirudin is a polypeptide consisting of 20 amino acids, the amino acid sequence is as follows: D- 1 Phe-Pro-Arg-Pro- 5 Gly-Gly-Gly-Gly- 9 Asn-Gly-Asp-Phe-Glu-Glu- 15 Ile-Pro-Glu-Glu-Tyr- 20 Leu-OH. [0004] There are a large number of reports at h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/08C07K1/04
Inventor 张颖刘鹏李同金朱玉正石鑫磊高国锐姜寿俊孙健刘元鑫王学斌李洪爽郑良文
Owner JINAN KANGHE MEDICAL TECH
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