Technical method for synthesizing bivalirudin protected pentapeptide fragment by mass high-performance liquid chromatography method

A technology of high-efficiency liquid phase and process method, which is applied in the field of high-volume high-efficiency liquid phase synthesis of bivalirudin protected pentapeptide fragments, which can solve the problems of difficult purification, easy production of impurities, and low yield, and achieve controllable impurities , less environmental pollution and high yield

Active Publication Date: 2019-08-30
JINAN ASIA PHARMA TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the problems that the preparation method of the prior art is easy to produce impurities, difficult to purify, low yield, high cost, etc., the present invention provides a process for synthesizing bivalirudin pentapeptide fragments by high-efficiency liquid phase method in large batches to solve the above technical problems question

Method used

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  • Technical method for synthesizing bivalirudin protected pentapeptide fragment by mass high-performance liquid chromatography method
  • Technical method for synthesizing bivalirudin protected pentapeptide fragment by mass high-performance liquid chromatography method

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Effect test

Embodiment 1

[0045] A process method for synthesizing bivalirudin-protected pentapeptide fragments by high-efficiency liquid phase method in large batches, the specific steps are as follows:

[0046] (1) Synthesis of tripeptide Fmoc-Pro-2Gly-OH

[0047] Fmoc-Pro-OSu+H-Gly-Gly-OH(Na 2 CO 3 )→Fmoc-Pro-2Gly-OH

[0048] Add sodium carbonate (42.4g, 0.4mol) to 300 ml of purified water, stir to dissolve, add bisglycine peptide (27g, 0.2mol) and stir to dissolve, after stirring to dissolve, add Fmoc-Pro-OSu (87g) dropwise , 0.2mol) solution of dioxane (300 ml), dripping is completed, after 6 hours of reaction, spot plate detection Fmoc-Pro-OSu reaction is complete. Add 1200 mL of purified water to the reaction solution, stir evenly, adjust the pH of the reaction solution between 2-3 with 3M hydrochloric acid solution, stand for crystallization, suction filtration, wash with purified water until the product is neutral, and dry to obtain the tripeptide Fmoc-Pro- 2Gly-OH 75.0 g (0.17 mol), purity ...

Embodiment 2

[0055] A process method for synthesizing bivalirudin-protected pentapeptide fragments by high-efficiency liquid phase method in large batches, the specific steps are as follows:

[0056] (1) Synthesis of tripeptide Fmoc-Pro-2Gly-OH

[0057] Fmoc-Pro-OSu+H-Gly-Gly-OH(NaHCO 3 )→Fmoc-Pro-2Gly-OH

[0058] Add sodium bicarbonate (33.6g, 0.4mol) to 300 ml of purified water, stir to dissolve, add glycine peptide (27g, 0.2mol) and stir to dissolve, after stirring to dissolve, add Fmoc-Pro-OSu ( 87g, 0.2mol) solution of dioxane (150ml), dripping is completed, after 8 hours of reaction, spot plate to detect that the reaction of Fmoc-Pro-OSu is complete. Add 1200 mL of purified water to the reaction solution, stir evenly, adjust the pH of the reaction solution between 2-3 with 3M hydrochloric acid solution, stand for crystallization, suction filtration, wash with purified water until the product is neutral, and dry to obtain the tripeptide Fmoc-Pro- 2Gly-OH 60.1 g (0.136 mol), purity ...

Embodiment 3

[0065] A process method for synthesizing bivalirudin-protected pentapeptide fragments by high-efficiency liquid phase method in large batches, the specific steps are as follows:

[0066] (1) Synthesis of tripeptide Fmoc-Pro-2Gly-OH

[0067] Fmoc-Pro-OSu+H-Gly-Gly-OH(NaHCO 3 )→Fmoc-Pro-2Gly-OH

[0068] Add sodium carbonate (42.4g, 0.4mol) to 300 ml of purified water, stir to dissolve, add bisglycine peptide (27g, 0.2mol) and stir to dissolve, after stirring to dissolve, add Fmoc-Pro-OSu (87g) dropwise , 0.2mol) methanol (300 ml) solution, dripping is completed, after 8 hours of reaction, spot plate detection Fmoc-Pro-OSu reaction is complete. Add 1200 mL of purified water to the reaction solution, stir evenly, adjust the pH of the reaction solution between 2-3 with 3M hydrochloric acid solution, stand for crystallization, suction filtration, wash with purified water until the product is neutral, and dry to obtain the tripeptide Fmoc-Pro- 2Gly-OH 55.8g (0.126mol), purity 97.4...

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Abstract

The invention relates to the technical field of bivalirudin, and particularly relates to a technical method for synthesizing bivalirudin protected pentapeptide fragment by a mass high-performance liquid chromatography method. According to the method, Fmoc-Pro-OSu is used as an initial raw material, is condensed with dipeptide to obtain a protected tripeptide; and the protected tripeptide is condensed with dipeptide, and recrystallization is performed to obtain the compound. The method has the advantage of mild reacting condition, the production requirement can be met by conventional productionconditions; the product is refined by adopting a crystallization method, has low cost, simple operation and high yield in comparison with column chromatography; and hydrofluoric acid and other fluorine-containing compounds are not use, and environmental pollution is small.

Description

technical field [0001] The invention relates to the technical field of bivalirudin, in particular to a process method for synthesizing bivalirudin-protected pentapeptide fragments by a large-scale high-efficiency liquid phase method. Background technique [0002] Bivalirudin, a hirudin derivative fragment, was approved by the US FDA in 2000. Bivalirudin is a direct thrombin inhibitor, which specifically binds to the catalytic site of thrombin in the blood circulation or to the substrate recognition site, and temporarily inhibits the active site of thrombin, which can directly inhibit the activity of thrombin. Bivalirudin has many advantages in clinical use. It can specifically and directly inhibit thrombin activity with strong specificity; its half-life is short, and it has a reversible inhibitory effect on thrombin, and its anticoagulant effect is predictable; the drug has mild It can also be used in patients with impaired renal function without adjusting the treatment pla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/815C07K1/30C07K1/06C07K1/02
CPCC07K14/815Y02P20/55
Inventor 彭立增孙秀伟姬松涛刘晓斐姚小军梁丽娴刘焕香白启峰
Owner JINAN ASIA PHARMA TECH
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