Method for preparing linaclotide

A technology of linaclotide and crude peptide, which is applied in the field of preparation of linaclotide, can solve the problems of inability to form three pairs of disulfide bonds with complete selectivity, unable to obtain target products, unsatisfactory results, etc., and achieves considerable economy. The effect of practical value, easy post-processing and low cost

Inactive Publication Date: 2014-03-12
HYBIO PHARMA
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AI Technical Summary

Problems solved by technology

In the first group of experiments, the final result of the [2Mmt+2Acm+2Trt] strategy was that the target product could not be obtained; the result of the [2Acm+2Trt+2pMeOBzl] method was also very unsatisfactory and eventually failed; the [2StBu+2Trt+2pMeOBzl] method, the research In the end, the target product was still not obtained, and it was concluded that linaclotide could not form three pairs of disulfide bonds with complete selectivity.

Method used

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  • Method for preparing linaclotide

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of the Fmoc-Tyr(tBu)-Wang Resin that the degree of substitution is 0.51mmol / g

[0037]Weigh 100 grams of Wang Resin with a substitution degree of 1.0 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen bubbles for 60 minutes; weigh 45.9 grams (100 mmol) of Fmoc-Tyr(tBu)-OH, HOBt16.2 gram (120mmol), DMAP 1.2g (10mmol), dissolved in DMF, 20.3ml DIC (120mmol) was added in an ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, after 2 hours of reaction, 70ml acetic anhydride and 60ml pyridine were added , mixed and sealed for 24 hours, washed with DCM three times, and the resin was dried after shrinking with methanol to obtain Fmoc-Tyr(tBu)-Wang Resin, and the detection substitution degree was 0.51mmol / g.

Embodiment 2

[0038] Embodiment 2: the preparation of the Fmoc-Tyr(tBu)-Wang Resin that the degree of substitution is 0.56mmol / g

[0039] Weigh 100 grams of Wang Resin with a substitution degree of 1.0 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen bubbles for 60 minutes; weigh 45.9 grams (100 mmol) of Fmoc-Tyr(tBu)-OH, HOBt16.2 gram (120mmol), DMAP1.2g (10mmol), dissolved in DMF, 40.6ml DIC (240mmol) was added in ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, after 2 hours of reaction, added 70ml acetic anhydride and 60ml pyridine , mixed and blocked for 24 hours, washed with DCM three times, dried the resin after shrinking with methanol to obtain Fmoc-Tyr(tBu)-Wang Resin, and the detection substitution degree was 0.56mmol / g.

Embodiment 3

[0040] Embodiment 3: the preparation of the Fmoc-Tyr(tBu)-Wang Resin that the degree of substitution is 0.63mmol / g

[0041] Weigh 100 grams of Wang Resin with a substitution degree of 1.0 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen bubbles for 60 minutes; weigh 45.9 grams (100 mmol) of Fmoc-Tyr(tBu)-OH, HOBt16.2 gram (120mmol), HBTU38.0g (100mmol), DMAP1.2g (10mmol), dissolved in DMF, added 25.6ml DIPEA (120mmol) in ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, reacted for 2 hours , add 70ml of acetic anhydride and 60ml of pyridine, mix and seal for 24h, wash with DCM three times, drain the resin after shrinking with methanol, and obtain Fmoc-Tyr(tBu)-Wang Resin, the detection substitution degree is 0.63mmol / g.

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Abstract

The invention belongs to the technical field of medicine synthesis, and discloses a method for synthesizing linaclotide by three pairs of total selectively formed disulfide bonds. By using the process, formation of three pairs of disulfide bonds in linaclotide can be sequentially completed in the same solution system, so that the operation method of the process is simple, the yield of final fine peptide of linaclotide can be greatly increased, and large-scale production can be realized.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of linaclotide. Background technique [0002] Linaclotide, the English name is Linaclotide; the trade name is Linzess; the Chinese common name is Linaclotide. It is a GC-C (intestinal cell uridine 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 (IBS) -C). The drug was developed by Ironwood Pharmaceuticals. The compound structure is a polypeptide composed of 14 amino acids containing three pairs of disulfide bonds (the three pairs of disulfide bonds are: 1-6; 2-10 and 5-13), which can be expressed by cells and chemical synthesis, the specific peptide sequence is shown in the following formula: [0003] [0004] At present, there is no relatively efficient preparation method for linaclotide, and there are no rele...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/20C07K1/06C07K1/04
CPCY02P20/55
Inventor 戴政清刘剑马亚平袁建成
Owner HYBIO PHARMA
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