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Preparation method of plecanatide

A technology of plecanatide and peptide fragments, which is applied in the field of preparation of polypeptide compound plecanatide, can solve the problems of poor direct coupling effect of N-terminal amino acids, long reaction time, cumbersome processing, etc., and achieves strong practical application value, The effect of low separation and purification difficulty and simple solution components

Pending Publication Date: 2021-06-11
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN201280021221.6 uses the fragment method to form the main chain through liquid phase condensation between the fragments. This method needs to prepare more than two fragments in advance, and the liquid phase condensation between the fragments is cumbersome to deal with, so it is not suitable for industrial production
The method of solid-phase synthesis of the main chain requires a high multiple of material input, resulting in a large amount of waste of raw materials, low utilization of raw materials, long reaction time, and due to the particularity of plecanatide, the direct coupling effect of N-terminal amino acids is poor

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: A kind of preparation method of plecanatide

[0052] 1. Preparation of BocAA1-4OH peptide fragment

[0053] (1) BocAA1-4OH peptide fragment sequence

[0054] Boc-Asn(trt)-Asp(OtBu)-Glu(OtBu)-Cys(Acm)-OH

[0055] (2) Synthesis of Fmoc-Cys(Trt)-CTC resin

[0056] Weigh 2.76g of 2-chlorotrityl chloride resin (CTC resin) with a degree of substitution of 1.1mmol / g into the polypeptide reactor, and add 27ml of DCM at the same time to wash and swell the resin for 1 hour. Weigh Fmoc-Cys(Acm)-OH (9mmol, 3.80g), add 19ml DCM to dissolve, add the dissolved reaction solution to the resin, and after the resin and the reaction solution are stirred evenly, add DIEA (13.5 mmol, 3.38ml), reacted at 25°C for 2 hours. After the reaction was completed, 2.21 ml of methanol was further added to the reaction solution to block unreacted active sites, and the reaction was performed for 1 hour. After the reaction was completed, the solution was drained, and the resin was washe...

Embodiment 2

[0080] Embodiment 2: A kind of preparation method of plecanatide

[0081] 1. Preparation of BocAA1-6OH peptide fragment

[0082] (1) BocAA1-6OH peptide fragment sequence

[0083] Boc-Asn(trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-Leu-OH

[0084] (2) Synthesis of Fmoc-Leu-CTC resin

[0085] Weigh 2.73g of CTC resin with a degree of substitution of 1.1mmol / g and add it into the polypeptide reactor, while adding 27ml of DCM to wash and swell the resin for 1 hour. Weigh Fmoc-Leu-OH (9mmol, 3.18g), add 19ml DCM to dissolve, add the dissolved reaction solution to the resin, after the resin and the reaction solution are stirred evenly, add DIEA (13.5mmol, 3.38g) to the resin reaction solution ml), react at 25°C for 2 hours. After the reaction was completed, 2.3 ml of methanol was further added to the reaction solution to block unreacted active sites, and the reaction was performed for 1 hour. After the reaction was completed, the solution was drained, and the resin was washed 4...

Embodiment 3

[0109] Embodiment 3: A kind of preparation method of plecanatide

[0110] 1. Preparation of BocAA1-8OH peptide fragment

[0111] (1) BocAA1-8OH peptide fragment sequence

[0112] Boc-Asn(trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-Leu-Cys(Acm)-Val-OH

[0113] (2) Synthesis of Fmoc-Val-CTC resin

[0114] Weigh 2.75g of CTC resin with a substitution degree of 1.1mmol / g and add it into the polypeptide reactor, while adding 27ml of DCM to wash and swell the resin for 1 hour. Weigh Fmoc-Val-OH (9mmol, 3.08g), add 19ml DCM to dissolve, add the dissolved reaction solution to the resin, and after the resin and the reaction solution are evenly stirred, add DIEA (13.5mmol, 3.36 ml), react at 25°C for 2 hours. After the reaction was completed, 2.3 ml of methanol was further added to the reaction solution to block unreacted active sites, and the reaction was performed for 1 hour. After the reaction was completed, the solution was drained, washed 4 times with 27 ml, and the resin was ...

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Abstract

The invention discloses a method suitable for industrially preparing pukanatide. According to the method, only two peptide fragments need to be prepared, the two peptide fragments are condensed into linear plecanatide through solid-phase synthesis, compared with a liquid-phase synthesis method, solution components are simpler, the separation and purification difficulty is lower, expensive enzymes are not needed, the cost is low, operation is convenient, and the method has high practical application value and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of polypeptide pharmacy, in particular to a preparation method of the polypeptide compound plecanatide. Background technique [0002] Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are two of the most common disorders affecting the gastrointestinal tract and are characterized by decreased stool frequency, straining, abdominal pain or discomfort. Chronic constipation in adults in my country, including CIC, functional defecation disorder and IBS-C, has a prevalence rate of 4%-6%, and 10 million to 15 million visits. Chronic constipation can be secondary to mental and psychological disorders, and the degree of damage to the quality of life of patients is comparable to that of chronic diseases such as diabetes and heart failure. [0003] Plecanatide (plecanatide) was developed by the Synergy Pharmaceutical Company of the United States. It is a cyclic polypeptide containing 16...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/08C07K1/06C07K1/04
CPCC07K7/08Y02P20/55
Inventor 戚建英康艳萍刘磊张才荣杨燕苹王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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