Method for preparing plecanatide

A technology of canatide and puna, applied in the field of polypeptide drug preparation, can solve the problems of long cycle, high cost, complicated process route, etc., and achieve the effect of solving polycondensation and increasing reactivity

Inactive Publication Date: 2021-05-28
杭州多普源生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process can well avoid the polycondensation problem of pure solid-phase synthesis and obtain high-quality final products, but the process route is very cumbersome and requires multi-step intermediate purification and post-treatment, making the cycle of single batch production very short. Long time, high staff occupation and high cost

Method used

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  • Method for preparing plecanatide
  • Method for preparing plecanatide
  • Method for preparing plecanatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of (2R / S,4R)-2-(2,4-dimethoxyphenyl)-thiazole-4-carboxylic acid

[0039] Add 12g of cysteine ​​and 16.6g of 2,4-dimethoxybenzaldehyde into 100mL of water and 100mL of mixed solvent, add 13.6g of water and sodium acetate, stir to form a homogeneous reaction solution, After stirring at room temperature for two hours, a large amount of white solid gradually formed. After 12 hours, the reaction was stopped, filtered, and the obtained paste solid was washed three times with water, washed three times with ethanol, dried to constant weight, and pulverized to obtain 22.5g of (2R / S,4R)-2-(2, 4-Dimethoxyphenyl)-thiazole-4-carboxylic acid, white solid, yield 75%.

Embodiment 2

[0041] Synthesis of Fmoc-(Dmp,DL)Cys-OH

[0042] Dissolve 22.5 g of (2R / S, 4R)-2-(2,4-dimethoxyphenyl)-thiazole-4-carboxylic acid obtained in Example 1 in 400 mL of DMF, add 42.5 g of Fmoc -OSu, cooled to 0-5 degrees, 40mL of DIEA is slowly added dropwise to the reaction solution, after the dropwise addition is completed, the entire reaction solution is warmed up to 25 degrees, and after 5 hours of reaction, the HPLC detection reaction has been completed. Add 400mL of dichloromethane to the mixture, wash with water three times, dry the organic phase and spin dry, add 250mL MTBE to the solid, filter after beating for 3 times, and dry the filter cake to constant weight to get the product Fmoc-(2R / S, 4R)-2-(2,4-dimethoxyphenyl)-thiazole-4-carboxylic acid, namely Fmoc-(Dmp,DL)Cys-OH, the yield is 83%.

Embodiment 3

[0044] Synthesis of Fmoc-Ala-(Dmp,DL)Cys-OH

[0045] Dissolve 10 g of (2R / S, 4R)-2-(2,4-dimethoxyphenyl)-thiazole-4-carboxylic acid obtained in Example 1 in 150 mL of DMF, add 15 g of Fmoc-Ala -OSu, cooled to 0-5 degrees, slowly dripping 18mL of DIEA into the reaction solution, after the dropwise addition, the whole reaction solution was warmed up to 25 degrees, and after 5 hours of reaction, the HPLC detection reaction was completed. Add 400mL of dichloromethane to the mixture, wash with water three times, dry the organic phase and spin dry, add 250mL MTBE to the solid, filter after beating for 3 times, and dry the filter cake to constant weight to obtain the product Fmoc-Ala-(Dmp, DL) Cys-OH, yield 77%.

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Abstract

An embodiment of the invention discloses a method for preparing plecanatide. The method is a novel process route for preparing plecanatide. According to the method, cysteine at a key position in a sequence adopts a special fragment and structure, so the polycondensation of a polypeptide sequence can be broken in a long distance, and the all-solid-phase large-scale production of the linear structure is realized. The plecanatid linear peptide obtained by the method has extremely high purity, and a crude product obtained by primary cyclization and secondary cyclization also has extremely high purity, is convenient to purify and is beneficial to the development of commercial large-scale production.

Description

technical field [0001] The invention relates to the technical field of polypeptide drug preparation, in particular to a method for preparing punacanatide. Background technique [0002] Peptide drugs have been sought after by the pharmaceutical industry for their high activity, low toxicity, and good druggability since their birth. At present, the biggest bottleneck restricting the marketing of peptide drugs is their commercial production cost, quality and batch size. [0003] The chemical synthesis of peptides can be divided into solid-phase synthesis, liquid-phase synthesis and solid-liquid combination strategies. Solid-phase synthesis is widely used in the industry because of its short cycle and no need for separation and purification of intermediates. However, solid-phase synthesis has long been plagued by polycondensation of peptides. The so-called polycondensation is the association of hydrogen bonds between peptide chains during the synthesis of peptides. The existenc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/04C07K1/06
CPCC07K7/08Y02P20/55
Inventor 卓壮壮
Owner 杭州多普源生物科技有限公司
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