Solid-phase fragment synthesis method of plecanatide

A synthetic method, the technology of Prica, is applied in the field of polypeptide drug preparation, which can solve the problems of strong hydrophobicity, difficult coupling, and low coupling efficiency, and achieve the effects of less by-products, beneficial purification, and avoiding low efficiency

Inactive Publication Date: 2019-02-19
ZHEJIANG SUPOR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a solid-phase fragment synthesis method of plekanatide, to overcome the problems of diffi

Method used

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  • Solid-phase fragment synthesis method of plecanatide
  • Solid-phase fragment synthesis method of plecanatide
  • Solid-phase fragment synthesis method of plecanatide

Examples

Experimental program
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Example Embodiment

[0092] Example 1: Synthesis of Fmoc-Leu-CTC resin with a substitution degree of 0.30 mmol / g.

[0093] Weigh 20.0g of 2-CTC resin with a substitution degree of 0.50mmol / g, add it to a solid-phase reaction column, wash it once with DMF, swell the resin with DCM for 30 minutes, and wash it three times with DMF, and take 10.6g of Fmoc-Leu- OH was dissolved in DCM, activated by adding 9.9ml DIEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, reacted for 2 hours, washed 3 times with DMF, and sealed with DIEA:MeOH:DCM = 1:10:20 mixture Overnight, DCM and methanol were alternately washed, shrunk and dried to obtain Fmoc-Leu-CTC resin with a detection degree of substitution of 0.30 mmol / g.

Example Embodiment

[0094] Example 2: Synthesis of Fmoc-Val-CTC resin with a substitution degree of 0.50 mmol / g.

[0095] Weigh 62.5g of 2-CTC resin with a substitution degree of 0.80mmol / g, add it to a solid-phase reaction column, wash it once with DMF, swell the resin with DCM for 30 minutes, and wash it three times with DMF, and take 50.9g of Fmoc-Val- OH was dissolved in DCM, activated by adding 49.6ml DIEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, reacted for 2 hours, washed 3 times with DMF, and sealed with a mixture of DIEA:MeOH:DMF=1:10:20 Overnight, DCM and MeOH were alternately washed, shrunk and dried to obtain Fmoc-Val-CTC resin with a detection substitution degree of 0.50 mmol / g.

Example Embodiment

[0096] Implementation Case 3: Preparation of two groups of 8-peptides of pulikanatide

[0097] Weigh 10.0g (3mmol) Fmoc-Leu-CTC resin with a degree of substitution of 0.30mmol / g, add it to the solid-phase reaction column, wash once with DMF, and swell the Fmoc-Leu-CTC resin with DCM for 30 minutes, then use DMF: The mixed solution with piperidine volume ratio 4:1 removes Fmoc protection, and then washes with DMF 6 times, weighs 3.7g Fmoc-Cys(Acm)-OH, 1.2g HOBt, adds DMF solution to dissolve, and adds 1.4ml DIC under ice-water bath to activate, Add it to the above-mentioned reaction column filled with resin, react at room temperature for 2 hours, use ninhydrin to detect and judge the end of the reaction, if the resin is colorless and transparent, it means the reaction is complete; if the resin develops color, the reaction is incomplete, and you need to continue the reaction Re-dosing in 1 hour or a single dose or changing the condensation reagent. Ninhydrin detection is suitab...

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Abstract

The invention discloses a solid phase fragment synthesis method of plecanatide. Firstly, the solid-phase synthesis method is used for coupling protective amino acids from a carbon end to a nitrogen end one by one on a solid-phase resin carrier under the condition of a condensation reagent, and an octapeptide fragment and octapeptide resin are obtained through synthesis; then, solid-phase condensation is conducted to obtain hexadecane resin, and the removal of an R protection group and resin cleavage are selectively carried out synchronously or sequentially according to the characteristics of the R protection group in the hexadecane resin; finally, two pairs of disulfide bonds are sequentially and directionally cyclized to form crude plecanatide, and then the crude plecanatide is purified by a preparative liquid phase and lyophilized to obtain the high-purity plecanatide. The method greatly shortens the synthesis cycle, avoids the problem of low efficiency in traditional methods in which solid phases are sequentially coupled with one another one by one, and also avoids the problem of complicated and cumbersome procedures in liquid-phase methods, correspondingly the cost is greatly reduced, the purity is high, few by-products are generated, and orientation is stable and accurate; the method is conducive to the purification of products, high in product yield and capable of facilitating large-scale production operation.

Description

technical field [0001] The invention belongs to the technical field of preparation of polypeptide drugs, and in particular relates to a method for synthesizing solid-phase fragments of plecanatide. Background technique [0002] Plecanatide, English name: plecanatide, its structure is as follows: [0003] [0004] Plecanatide is an analogue of uroguanylin, a cyclic polypeptide containing sixteen amino acids, which acts as a natriuretic guanylate cyclase receptor agonist and can Regulate the acid-base ions in the gastrointestinal tract, induce fluid transport into the gastrointestinal tract, increase the peristalsis of the gastrointestinal tract, and are suitable for the treatment of chronic idiopathic constipation in adults. The U.S. Food and Drug Administration (FDA) approved the listing on January 19, 2017, under the trade name Trulance. [0005] The current chemical synthesis method of plecanatide is as follows: [0006] 1) Coupling one by one on the solid phase to f...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/06C07K1/04
CPCC07K7/08Y02P20/55
Inventor 范小军陶伟锋陈鹏朱志敏章军杰陈忠根
Owner ZHEJIANG SUPOR PHARM CO LTD
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