Method used for preparing semaglutide

A peptide resin and resin technology, applied in the field of synthesizing semaglutide, can solve the problems of large steric hindrance, difficulty in synthesizing amino acids and dipeptides, and increasing the difficulty of coupling, achieve efficient coupling reaction, avoid polycondensation problems, reduce Effects of Synthetic Difficulty

Inactive Publication Date: 2018-06-26
上海脉凯生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the use of these methods will bring some new problems in the actual process, such as the

Method used

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  • Method used for preparing semaglutide
  • Method used for preparing semaglutide
  • Method used for preparing semaglutide

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Embodiment 1 Fmoc-Gly 37 -Synthesis of Wang Resin

[0042] Weigh 150 g of Wang resin with a degree of substitution of 0.82 mmol / g, add it to a solid-phase reaction vessel, wash it three times with DMF, add DMF to swell for 30 minutes, mix 36.6 g of Fmoc-Gly-OH, 19.6 g of HOBt, and 72.0 mL of DIC was activated at low temperature for 15 minutes and added. After 5 minutes of reaction with nitrogen gas, 1.9g of DMAP was added. After 2 hours of reaction, it was washed 3 times with DMF and 3 times with DCM, and capped with 480mL of 1:1 acetic anhydride / pyridine solution. After 3 hours, wash the resin 5 times with DMF, wash it 2 times with DCM, add methanol to shrink the resin, and dry to obtain 172.8 g of Fmoc-Gly-OH Wang resin, whose substitution degree is 0.39mmol / g detected by UV spectrophotometer .

Embodiment 2

[0043] Example 2 Synthesis of the first peptide resin

[0044] Weigh 45 g of Fmoc-Gly-Wang resin with a substitution degree of 0.39 mmol / g and add it to a solid-phase reaction vessel, wash it with DMF three times, add DMF to swell for 30 minutes, add 20% piperidine DMF solution, react for half an hour, and use DMF After washing 3 times and washing 3 times with DCM, the ninhydrin detection resin turns blue. After activating Fmoc-Arg(Pbf)-OH (34.1g, 52.65mmol), HOBt (7.15g, 52.65mmol) and DIC (6.7g, 52.65mmol) in low temperature DMF for 15 minutes, they were added to the resin at room temperature After 2 hours of reaction, the ninhydrin method was used to detect that the resin was colorless, indicating that the reaction was complete. After washing 4 times with DMF, it was washed twice with DCM.

[0045] Repeat the above steps of removing Fmoc and adding corresponding amino acid coupling, and complete Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gly-OH, Fmoc-Arg( Pbf)-OH, Fmoc-Val-OH, F...

Embodiment 3

[0046] Example 3 Using Mtt-Lys(Fmoc)-OH as raw material to synthesize the second peptide resin

[0047] Weigh Mtt-Lys(Fmoc)-OH (43.9g, 70.2mmol), DIC (8.9g, 70.2mmol), HOBt (9.5g, 70.2mmol), after activation at low temperature for 15 minutes, add to the first peptide resin After 2 hours of reaction, the resin was detected to be colorless with ninhydrin, and the reaction was completed. Wash the resin 4 times with DMF and 2 times with DCM, then add 20% piperidine DMF solution, react for half an hour, and wash with DMF After washing 3 times with DCM, the ninhydrin detection resin turns blue. Weigh Fmoc-AEEA-OH (27.0g, 70.2mmol), DIC (8.9g, 70.2mmol), HOBt (9.5g, 70.2mmol), activate at low temperature for 15 minutes, add to the peptide resin, and react for 2 hours Finally, use ninhydrin to detect that the resin is colorless, and the reaction is complete. Wash the resin 4 times with DMF and 2 times with DCM, add 20% piperidine DMF solution, react for half an hour, wash 3 times wit...

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Abstract

The invention belongs to the technical field of polypeptide synthesis, and especially relates to a synthesis method of semaglutide. The synthesis method comprises following steps; 1, prior coupling oflys26 side chain is carried out; and 2, O-iso-acylated dipeptide is adopted to break the secondary structure of beta-sheet in semaglutide synthesis process effectively so as to avoid polycondensationin polypeptide synthesis process, and then O to N transfer reaction is adopted to convert esterified semaglutide into semaglutide. The method is capable of reducing product synthesis difficulty, avoiding generation of a plurality of impurities, ensuring the product quality of semaglutide bulk drugs, increasing product yield, increasing the scale of single batch semaglutide production, and realizing mass production of semaglutide.

Description

Technical field: [0001] The invention provides a method for synthesizing semaglutide, which can realize the large-scale chemical synthesis and production of semaglutide and the declaration of drugs. technical background: [0002] GLP-1 glucagon-like peptide is a family of incretins, which are secreted by intestinal L cells. It is a hormone secreted after meals and helps control blood sugar. The main metabolic reaction is that with meals It is released when blood sugar levels rise and stimulates insulin production, inhibits glucagon release and slows the rate at which nutrients are absorbed into the bloodstream. However, because GLP-1 is rapidly inactivated and degraded by an enzyme (DPP-4) in the body, GLP-1 cannot be directly used as a drug in the human body to control blood sugar. [0003] GLP-1 analogs are also GLP-1 receptor agonists, their activity is similar to GLP-1, and they have a high affinity with GLP-1 receptors, which can simulate the natural gastrointestinal h...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCY02P20/55C07K14/605
Inventor 不公告发明人
Owner 上海脉凯生物科技有限公司
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