Method for preparing semaglutide by liquid phase method on basis of soluble carrier

A soluble, liquid-phase method, applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve the problems of excessive waste of reactants, large consumption of raw materials, and difficulty in completeness, reducing the difficulty of purification and saving time. cost, the effect of reducing the generation of impurities

Inactive Publication Date: 2020-05-08
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As we all know, there are the following problems in the solid-phase method: 1. The reactions involved are all heterogeneous reactions, and the reaction time is long and difficult to carry out completely; the excessive amount of feed makes it waste more reactants; and the reaction prone to side effects
2. The solid-phase method is limited by the substitution value of the solid-phase resin carrier, and the overall yield is low; and there are many by-products in the middle of missing or adding a single amino acid residue, which makes the impurity prop

Method used

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  • Method for preparing semaglutide by liquid phase method on basis of soluble carrier
  • Method for preparing semaglutide by liquid phase method on basis of soluble carrier
  • Method for preparing semaglutide by liquid phase method on basis of soluble carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Preparation of 2,4-bis(behenyloxy)benzyl alcohol (tag carrier):

[0105] 1) Preparation of intermediate 2,4-bis(behenyloxy)benzaldehyde: Weigh 2,4-dihydroxybenzaldehyde (0.6g, 4.34mmol), potassium carbonate (6.0g, 43.4mmol), 1-Bromodocosane (3.5g, 9mmol) was added into DMF (30ml), and stirred overnight at 70°C under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (400ml) and stirred, filtered, and the filter cake was collected and dried to obtain 2,4-bis(behenyloxy)benzaldehyde (3.20g, yield 97.5%) .

[0106] 2) Preparation of tag carrier: Weigh the above-mentioned 2,4-bis(behenyloxy)benzaldehyde (3.0g, 3.97mmol) and dissolve it in a mixed solution of THF (60ml) and MeOH (6ml), and add to the solution Sodium borohydride (400mg, 10.57mmol) was added to it, and the reaction was stirred at 40°C for 2 hours under the protection of nitrogen. Add purified water (2-3ml) dropwise to the reaction solution until a brown-red so...

Embodiment 2

[0109] Preparation of Fully Protected Fragment 1:

[0110] 1) Preparation of Fmoc-Gly-O-tag: Weigh the tag carrier (2.27g, 3mmol) and dissolve it in DCM (60ml), add Fmoc-Gly-OH (1.34g, 4.5mmol), DIC (567mg , 4.5mmol), DMAP (73mg, 0.6mmol), stirred at room temperature for 30min, and monitored the end point of the reaction by TLC. A large amount of acetonitrile was added to the solution to precipitate crystals, and the crystals were collected by filtration to obtain the product Fmoc-Gly-O-tag (3.07 g, yield 98.8%).

[0111]2) Preparation of H-Gly-O-tag: Dissolve the above Fmoc-Gly-O-tag in THF (60ml) containing 1% DBU, add PIP (384mg, 3.6mmol) to the solution, and stir at room temperature for 5min , TLC method to monitor the reaction end point. A large amount of acetonitrile was added to the reaction solution to precipitate crystals, and the crystals were collected by filtration to obtain the product H-Gly-O-tag (2.40 g). The total yield of 1) and 2) was 98.3%.

[0112] 3) A ...

Embodiment 3

[0117] Preparation of fully protected fragment 2:

[0118] 1) Preparation of Fmoc-Asp(OtBu)-O-tag: Weigh the tag carrier (2.27g, 3mmol) and dissolve it in DCM (60ml), add Fmoc-Asp(OtBu)-OH (1.86g, 4.5 mmol), DIC (567 mg, 4.5 mmol), DMAP (73 mg, 0.6 mmol), stirred at room temperature for 30 min, and monitored the end point of the reaction by TLC. A large amount of acetonitrile was added to the solution to precipitate crystals, and the crystals were collected by filtration to obtain the product Fmoc-Asp(OtBu)-O-tag (3.40 g, yield 98.5%).

[0119] 2) Preparation of H-Asp(OtBu)-O-tag: Dissolve the above Fmoc-Asp(OtBu)-O-tag in THF (60ml) containing 1% DBU, add PIP (384mg, 3.6mmol ), stirred at room temperature for 5 min, and monitored the end point of the reaction by TLC. A large amount of acetonitrile was added to the reaction solution to precipitate crystals, and the crystals were collected by filtration to obtain the product H-Asp(OtBu)-O-tag (2.73 g). The total yield of 1) a...

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Abstract

The invention provides a method for preparing semaglutide by a liquid phase method on the basis of a soluble carrier. The invention solves the technical problems of tedious method, difficulty in purification and lower yield in a conventional solid phase method for preparing long-chain polypeptides like the semaglutide. According to the invention, the semaglutide is divided into six fragments whichare prepared by taking lipophilic and hydrophobic 2,4-di(docosaalkoxy)benzyl alcohol as a carrier through a one-by-one coupling method. The method provided by the invention is different from a traditional solid phase method, can simply monitor whether a reaction is completely carried out or not through TLC or a liquid phase method in the reaction, effectively avoids the loss or addition of singleamino acid residue impurities, effectively lowers the purification difficulty, enhances the utilization ratio of raw materials, and conforms to the green chemistry concept pushed nowadays. The methodprovided by the invention can also be widely applied to the technical field of preparation of polypeptide drugs.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation, in particular a method for preparing semaglutide by a liquid-phase method based on a soluble hydrophobic label carrier. Background technique [0002] The information disclosed in the Background of the Invention is only intended to increase the understanding of the general background of the invention, and is not necessarily to be taken as an acknowledgment or any form of suggestion that the information constitutes the prior art that is already known to those skilled in the art. [0003] Type II diabetes is currently a major chronic disease that endangers human health. Its main feature is that the human body can secrete insulin itself, but due to insulin resistance, it is difficult or impossible for human cells to respond to insulin, and the effect of insulin is significantly reduced, resulting in elevated blood sugar. . Currently, drugs for type II diabetes mainly include a s...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04C07K1/02
CPCC07K14/605Y02P20/55
Inventor 马淑涛刘兴邦
Owner SHANDONG UNIV
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