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Preparation method of plecanatide

A technology of Pulica and -OH, which is applied in the field of medicine, can solve the problems of low yield and achieve the effects of simple operation, environmental friendliness and simplified process

Active Publication Date: 2018-11-23
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lower yield due to formation of two pairs of disulfide bonds by directional oxidation on solid phase

Method used

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  • Preparation method of plecanatide
  • Preparation method of plecanatide
  • Preparation method of plecanatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the degree of substitution is the preparation of 0.50mmol Fmoc-Leu-Wang resin

[0052] Weigh 100 g of Wang resin with a substitution degree of 1.0 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen gas bubbles for 60 minutes; weigh 35.4 grams (100 mmol) of Fmoc-Leu-OH and 16.2 grams (120 mmol) of HOBt 1.2 g (10 mmol) of DMAP, dissolved in DMF, added 20.3 mL of DIC at 0°C, activated for 5 minutes, and added to the reaction column. After two hours of reaction, add 70mL of acetic anhydride and 60mL of pyridine, mix and seal for 24 hours, wash with DCM three times, dry the resin after shrinking with methanol, and obtain 130 grams of Fmoc-Leu-Wang resin, with a detection degree of substitution of 0.50mmol / g.

Embodiment 2

[0053] Embodiment 2: the preparation of peptide resin

[0054] Weigh 50 g of the Fmoc-Leu-Wang resin with a degree of substitution of 0.50 mmol / g prepared in Example 1 and place it in a solid-phase reaction column, add 50 mL of DMF, and swell with nitrogen bubbling for 60 minutes; Wash 6 times. Weigh 30.0g (75mmol) Fmoc-3-Cl-Ala-OH and 11.7g (75mmol) HOBT dissolved in 50mL DMF, add 13mL (75mmol) DIPCDI to activate for 3min under ice-water bath, then add the mixture into the reaction column, React at room temperature for 2 hours, and detect the end of the reaction with ninhydrin (if the resin is colorless and transparent, stop the reaction; if the resin develops color, extend the reaction for 1 hour). After the reaction is over, wash the resin with 100 mL DMF for 3 times, add 50 mL DBLK for deprotection for 6 min + 8 min, wash the resin with 100 mL DMF for 6 times, and detect the color of the resin with ninhydrin. Repeat the above coupling operation, and continue to couple Fm...

Embodiment 3

[0055] Embodiment 3: Peptide resin removes protecting group StBu

[0056] 500ml of DMF, 50mL of mercaptoethanol, and 30mL of N-methylmorpholine were sequentially added to 100.5g of the peptide resin obtained in Example 2, and reacted at 50°C for 18 hours. After the reaction was completed, the solution was drained under reduced pressure, and the resin was washed 3 times with 500mL DMF, without further treatment, directly entering the next step.

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PUM

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Abstract

The invention relates to a preparation method of plecanatide. The method comprises the following steps of (1) sequentially coupling Fmoc-AA-OH on solid phase synthesis resin; (2) removing StBu protection groups on Cys; (3) removing Cys oxidization formed rings of the StBu protection groups to obtain plecanatide precursor resin containing single disulfide rings; (4) performing pyrolysis on the solid phase synthesis resin; preparing plecanatide precursors containing single disulfide rings; (5) in liquid phase reaction, forming disulfide bonds by the 7-th and 15-th site 3-Cl-Ala in the plecanatide precursors containing single disulfide rings under the effects of vulcanizing agents so as to obtain plecanatide.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing plecanatide. Background technique [0002] Plecanatide, whose English name is plecanatide, CAS number: 467426-54-6, is a polypeptide drug composed of 16 amino acids, and its peptide sequence is shown in formula I: [0003] [0004] In its peptide sequence, the 4th cysteine ​​at the N-terminal forms a loop with the 12th cysteine, and the 7th cysteine ​​forms a loop with the 15th cysteine. [0005] On January 19, 2017, the U.S. FDA approved pulikanatide for the treatment of chronic idiopathic constipation in adult patients. The trade name is Trulance, and the development company is Synergy Pharmaceuticals in the United States. Plicanatide is a guanylate cyclase C (GC-C) receptor agonist with a therapeutic mechanism similar to that of the natriuretic peptide guanylin, which induces fluid secretion into the gastrointestinal tract, thereby increasing gastrointesti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/20C07K1/06C07K1/04
CPCC07K7/08C07K1/02C07K1/04C07K1/06C07K1/20C07K7/64Y02P20/55
Inventor 陈学明朱艳婷宓鹏程陶安进袁建成
Owner HYBIO PHARMA