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Synthetic method of linaclotide

A technology of linaclotide and synthetic method, which is applied in the field of drug synthesis, can solve the problems of low product purity and yield, and achieve the effects of low cost, simple operation and high yield

Active Publication Date: 2017-06-27
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The present invention aims at the problems in the above synthesis method that the purity and yield of the product are low due to the generation of isomer impurities due to mismatching of disulfide bonds, and provides a method for synthesizing Lina by completely selective formation of three pairs of disulfide bonds. Lopeptide method to achieve directional and efficient synthesis of three pairs of fully crossed disulfide bonds

Method used

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  • Synthetic method of linaclotide
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  • Synthetic method of linaclotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the degree of substitution is the preparation of 0.50mmol Fmoc-Tyr(tBu)-Wang resin

[0048] Take by weighing Wang resin 100g that the degree of substitution is 1.0mmol / g in the solid phase reaction column, add 150ml DMF, nitrogen bubbling swelling 60 minutes; Weigh Fmoc-Tyr (tBu)-OH (45.9g, 100mmol), HOBt ( 16.2g, 120mmol), DMAP (1.2g, 10mmol), dissolved in 100ml DMF, added DIC (20.3ml, 117.1mmol) at 0°C, activated for 5 minutes, and added to the reaction column. After two hours of reaction, acetic anhydride (70ml) and pyridine (60ml) were added, mixed and blocked for 24 hours, and washed with DCM 3 times (100ml / time). The resin was shrunk with methanol and dried to obtain 150 g of Fmoc-Tyr(tBu)-Wang resin, and the detected substitution degree was 0.50 mmol / g.

Embodiment 2

[0049] Embodiment 2: Preparation of linaclotide precursor resin

[0050] Take by weighing the Fmoc-Tyr (tBu)-Wang resin 50g (25mmol) that the degree of substitution prepared in Example 1 is 0.50mmol / g in the solid-phase reaction column, add 50ml DMF, nitrogen bubbling swelling 60 minutes; Then use DBLK to remove Protected 2 times (50ml / time), 6min and 8min respectively, and washed 6 times with DMF (100ml / time). Weigh Fmoc-Cys(Me)-OH (48.7g, 75mmol) and HOBt (11.7g, 75mmol) and dissolve them in 100ml DMF, add DIC (13ml, 75mmol) under ice-water bath to activate for 3min, then add the mixture to 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, prolong the reaction for 1 hour). After the reaction is over, wash the resin 3 times with DMF (100ml / time), add DBLK for deprotection 2 times (100ml / time), 6min and 8min respectively, was...

Embodiment 3

[0052] Embodiment 3: remove protecting group Mmt

[0053] 107.6 g of the linaclotide precursor resin obtained in Example 2 was swollen with 1 liter of DMF solution for 1 hour, the solution was removed under reduced pressure, and washed twice with DCM (500 ml / time). Resin is washed with the solution 250ml of 2%TFA / DCM (v / v), each 2 minutes, until resin color changes colorless by redness, washes 2 times (500ml / time) with DCM then, DMF washes 2 times (500ml / time), the solution was sucked off under reduced pressure.

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Abstract

The invention belongs to the technical field of drug synthesis and discloses a method for synthesizing linaclotide from three pairs of completely selectively formed disulfide bonds. The method comprises the followings steps: (1) synthesizing linaclotide precursor resin in a solid phase manner; (2) carrying out solid-phase oxidation, so as to form a first pair of disulfide bonds; (3) carrying out liquid-phase oxidation, so as to form a second pair of disulfide bonds; and (4) removing methyl from methyl-protected cysteine, and simultaneously carrying out oxidative coupling on the third pair of disulfide bonds, so as to obtain linaclotide. The method has the beneficial effects that reaction conditions are mild, the cost is low, the yield is high, the product purity is high, and the process is simple, stable and suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of linaclotide. Background technique [0002] Linaclotide is a GC-C (intestinal cell uridylate cyclase C) receptor agonist, approved by the US FDA in August 2012 for the treatment of adults with chronic idiopathic constipation and constipation-predominant irritable bowel syndrome Syndrome (IBS-C). The drug was developed by Ironwood Pharmaceuticals. The structure of the compound is a polypeptide consisting of 14 amino acids and containing three pairs of disulfide bonds. It can be produced through cell expression and chemical synthesis. Its structure is as follows: [0003] [0004] Benitez et al. reported on Peptide Science in 2010. Three methods have been used in the literature to try to synthesize linaclotide. Method (1): Use Trt as the side chain protecting group of Cys, and use Fmoc solid-phase peptide synthesis method to complete the synthesis ...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/06C07K1/04
CPCC07K7/08C07K1/067C12Y111/01007C07K1/04C07K1/042C07K1/06C07K1/16C07K1/20C07K7/64C12P21/02Y02P20/55
Inventor 陈学明吴靖康宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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