Preparation method of plecanatide

A technology of pika and peptide resin, applied in the field of preparation of pikatide, can solve problems such as the impact of patients' work and quality of life, and achieve the effects of being conducive to subsequent purification, less solvent usage, and high automation rate

Inactive Publication Date: 2014-12-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

Both CC and IBS-C are common gastrointestinal disorders that can

Method used

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  • Preparation method of plecanatide

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Experimental program
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Embodiment 1

[0038] Embodiment 1: the synthesis of the Fmoc-Leu-Wang resin that substitution degree is 0.3mmol / g

[0039] Weigh 400 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 84.84g Fmoc-Leu-OH (240mmol), 38.88g HOBt (288mmol) and 2.93g DMAP (24mmol) in 800ml of DCM and DMF (1:1 volume ratio) mixed solution, add 45.02ml under ice-water bath DIC (288mmol) was activated for 3 minutes and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 1395ml blocking solution (pyridine / acetic anhydride=1:1, 8mol:8mol) to block for 8 hours. Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Leu-Wang resin. The degree of substitution was detected to be 0.297mmol / g (the method for detecting the degree of substitution of the resin in this article can refer to "Solid Phase Organic Syn...

Embodiment 2

[0040] Embodiment 2: the synthesis of the Fmoc-Leu-Wang resin that substitution degree is 0.4mmol / g

[0041] Weigh 400 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 113.12g Fmoc-Leu-OH (320mmol), 51.84g HOBt (384mmol) and 3.90g DMAP (32mmol) in 800ml of DCM and DMF (1:1 volume ratio) mixed solution, add 60.03ml under ice-water bath DIC (384mmol) was activated for 3min and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 1395ml blocking solution (pyridine / acetic anhydride=1:1, 8mol:8mol) to block for 8 hours. Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Leu-Wang resin. The detection degree of substitution was 0.403mmol / g.

Embodiment 3

[0042] Embodiment 3: the synthesis of the Fmoc-Leu-Wang resin that substitution degree is 0.5mmol / g

[0043]Weigh 400 g of Wang resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 141.40g Fmoc-Leu-OH (400mmol), 64.85g HOBt (480mmol) and 4.88g DMAP (40mmol) in 800ml of DCM and DMF (1:1 volume ratio) mixed solution, add 75.04ml under ice-water bath DIC (480mmol) was activated for 3 minutes and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 1395ml blocking solution (pyridine / acetic anhydride=1:1, 8mol:8mol) to block for 8 hours. Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Leu-Wang resin. The detected substitution degree was 0.511mmol / g.

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Abstract

According to the invention, plecanatide is synthesized by a solid-liquid combination method. Two disulfide bonds are successively formed by an orientation method. Thus, mismatching of disulfide bonds is avoided, and it is beneficial to subsequent purification. The method provided by the invention has advantages of simple operation, high automation and few usage amount of a solvent, and is green and environmentally friendly.

Description

technical field [0001] The invention relates to a preparation method of a polypeptide, in particular to a preparation method of picanatide. Background technique [0002] Plecanatide is a synthetic analogue of uroguanylin (uroguanylin is a natriuretic hormone that can regulate the transport of ions and liquids in the gastrointestinal tract). After entering the body, Plecanatide interacts with The guanylate cyclase C on the endothelial cells of the gastrointestinal mucosa binds and activates it, activates the cystic fibrosis transmembrane conductance regulator (CFTR), and promotes the entry of chloride and water into the intestine, thereby promoting intestinal peristalsis, Improve constipation symptoms. [0003] On October 6, 2010, Synergy announced the results of Phase IIa clinical trials of its new drug Picanatide (code: SP304) in the treatment of gastrointestinal diseases. The study in patients with chronic constipation showed that the drug improved bowel function, increa...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/06C07K1/04
CPCY02P20/55
Inventor 宓鹏程潘俊锋马亚平袁建成
Owner HYBIO PHARMA
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