Method for preparing semaglutide

The technology of semaglutide and resin is applied in the field of preparation of semaglutide, which can solve the problems of decreased economic benefit, decreased yield, side reactions, etc., so as to reduce the risk of His racemization, reduce the coupling synthesis steps, Reduce the effect of increasing the number of couplings

Inactive Publication Date: 2017-07-07
HYBIO PHARMA
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Problems solved by technology

It is mentioned in the patent that the experiment of removing Mmt and Mtt needs to be repeated 6-12 times, each time for 5-10 minutes. Repeated operations may cause other protective agents that are easily affected by acid, such as Trt, tBu, Boc, etc., may be damaged. Lead to the generation of side reactions; Mmt, Mtt protecting groups are difficult to remove, and it is difficult to ensure that the protective groups are completely removed during the scale-up production process; 6-12 repeated operations make the experimental process cumbersome; when using 2-CTC (2- When triphenyl chloride resin) is used as the reaction carrier, the use of weak acid can easily cause the linker to fall off, the polypeptide fragment is excised, and the final yield is greatly reduced, resulting in an increase in production costs and a decline in economic benefits; Hydrazine solution needs to be used for removal. Hydrazine has strong reducibility and is easy to have side reactions with oxidizing groups. The lively nature of hydrazine has certain risks in storage and transportation, and there are potential safety hazards in the process of enlarging production.

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  • Method for preparing semaglutide
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  • Method for preparing semaglutide

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preparation example Construction

[0049] The invention discloses a preparation method of somaglutide, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention. The method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.

[0050] The present invention describes two methods for synthesizing somaglutide:

[0051] Method 1: Sequential coupling selection

[0052] Sequential coupling route map as figure 1 (B) shows:

[0053] Method 2: Sequential...

Embodiment 1

[0078] Example 1: Preparation of Fmoc-Gly-Wang Resin

[0079] Weigh 210g of dry Wang Resin (with a degree of substitution of 0.845mmol / g) into the solid phase reaction column, first wash the resin twice with DMF, then swell the resin with 2 to 3 times the volume of the resin bed for 30 minutes, and wash 3 times with DMF , DCM wash 2 times, waiting for feeding.

[0080] Under ice-cooling conditions, dissolve 105.48g Fmoc-Gly-OH and 47.92g HOBt in a mixed solvent of DMF and DCM. After the amino acid is dissolved, slowly add 55ml DIC, activate for 3min, and pour the reaction solution into the reaction. In the column, add 2.17g of DMAP, agitate and react for 2 hours; after the reaction, after washing with DMF 3 times, add an appropriate amount of acetic anhydride and pyridine mixed solution (volume ratio: Ac2O / Pyridine=7 / 6) to block the reaction for 5 hours Or above, after the reaction is stopped, DMF is washed 6 times, methanol is shrunk twice, and dried under reduced pressure to obt...

Embodiment 2

[0081] Example 2: Preparation of Fmoc-Gly-Wang Resin

[0082] Weigh 218g of dry Wang Resin (substitution degree is 0.845mmol / g) into the solid phase reaction column, first wash the resin with DMF 2 times, then swell the resin with 2 to 3 times the resin bed volume DMF for 30 minutes, and wash 3 times with DMF , DCM wash 2 times, waiting for feeding.

[0083] Under the condition of ice bath cooling, 26.88g Fmoc-Gly-OH and 12.03g HOBt are dissolved in a mixed solvent of DMF and DCM. After the amino acid is dissolved, slowly add 11ml DIC, activate for 3min, and pour the reaction solution into the reaction. In the column, add 1.12g of DMAP, stir the reaction for 45min with aeration; after the reaction, after washing with DMF for 3 times, add an appropriate amount of acetic anhydride and pyridine mixed solution (volume ratio: Ac2O / Pyridine=7 / 6) to block the reaction overnight, and react After stopping, DMF was washed 6 times, methanol was shrunk twice, and dried under reduced pressure ...

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Abstract

The invention relates to the field of polypeptides, in particular to a method for preparing semaglutide. The method has the advantages that Fmoc-Lys (Alloc)-OH protection amino acid is used as a raw material, de-protection is carried out by the aid of selected Pd (PPh3) 4, accordingly, operation procedures are simple, only 1-2 times of simple elimination reaction operation are required, each elimination reaction operation is carried out for 10-30 min, side reaction is prevented, the operation procedures are safe, and enlarged production can be facilitated; Boc-His (Boc)-OH. DCHA and Boc-His (Trt)-OH are used as raw materials in the procedures, and accordingly His racemization risks can be reduced to the greatest extent; special fragments are coupled, and accordingly the synthesis efficiency can be improved.

Description

Technical field [0001] The present invention relates to the field of polypeptides, in particular to a preparation method of somaglutide. Background technique [0002] The chemical structure of Somaglutide is as figure 1 As shown in (A): Semaglutide is a long-acting GLP-1 analog developed by Nove Nordisk. The drug only needs to be administered by subcutaneous injection once a week, and it is still in clinical phase III. From the structural point of view, Semaglutide needs to connect Lys at position 26 to aliphatic chain of PEG, glutamic acid and octadecanoic acid, of which the unnatural amino acid aminoisobutyric acid is used at position 8. Compared with Liraglutide, Semaglutide has a longer aliphatic chain and increased hydrophobicity, but Semaglutide has been modified with a short chain of PEG to greatly increase its hydrophilicity. After PEG modification, it can not only bind tightly to albumin, mask the DPP-4 enzymatic hydrolysis site, but also reduce renal excretion, prolong...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605C07K1/06C07K1/04C07K14/001
Inventor 陈新亮宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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