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Preparation method of semaglutide

A technology of semaglutide and semaglutide crude peptide, which is applied in the field of peptide drug preparation, can solve problems such as unfavorable large-scale production, Lys rearrangement, heavy metal residues exceeding the standard, etc., achieve extensive practical value and application prospects, and reduce difficulty and feed ratio, the effect of reducing the difficulty of refining

Inactive Publication Date: 2020-03-27
杭州肽佳生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When Lys adopts Mmt and Mtt, it needs to be removed by acidic solution such as TFA, and a certain capture agent needs to be added, and it needs to be repeatedly processed. Because the acidic solution is very corrosive to the equipment, it is not conducive to large-scale production
When using Dde protection, it is easy to cause the rearrangement of Lys, resulting in the generation of new impurities
When Alloc protection is used, heavy metal catalyst Pd(PPh 3 ) 4 Deprotection can easily cause heavy metal residues to exceed the standard

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of Fmoc-Gly-Wang Resin

[0028] The preparation method of Fmoc-Gly-Wang Resin with a substitution value of 0.4mmol / g is as follows:

[0029] Weigh 200g (100mmol) of Wang resin with a substitution value of 0.5mmol / g, add it to a solid-phase reactor, wash it twice with DMF, and after swelling the resin with DMF for 60 minutes, take 44.6g Fmoc-Gly-OH, 20.3g HOBt , 18.9g DIC, and 1.5g DMAP were dissolved in a mixed solution of DCM and DMF with a volume ratio of 1:1, added to a solid-phase reactor, and reacted at room temperature for 3 hours. After the reaction was completed, it was washed 3 times with DMF and 3 times with DCM. Then add a capping solution for capping for 30 minutes. The ratio of the capping solution is: acetic anhydride:DMF:DIEA=10:84:6 (V:V:V). After capping, it was washed 3 times with DMF and 3 times with DCM, then shrunk and dried with methanol to obtain Fmoc-Gly-Wang resin, and the detected substitution value was 0.4 mmol / g.

[0030] The s...

Embodiment 2

[0039] Preparation of Fmoc-Gly-Wang Resin

[0040] The preparation method of Fmoc-Gly-Wang Resin with a substitution value of 0.7mmol / g is as follows:

[0041] Weigh 100g (100mmol) of Wang resin with a substitution value of 1.0mmol / g, add it to a solid-phase reactor, wash it twice with DMF, and after swelling the resin with DMF for 60 minutes, take 59.4g Fmoc-Gly-OH, 27.0g HOBt , 25.2g DIC, and 2.4g DMAP were dissolved in a mixed solution of DCM and DMF with a volume ratio of 1:1, added to a solid-phase reactor, and reacted at room temperature for 3 hours. After the reaction was completed, it was washed 3 times with DMF and 3 times with DCM. Then add a capping solution for capping for 30 minutes. The ratio of the capping solution is: acetic anhydride:DMF:DIEA=10:84:6 (V:V:V). After capping, it was washed 3 times with DMF and 3 times with DCM, then shrunk and dried with methanol to obtain Fmoc-Gly-Wang resin with a detected substitution value of 0.7 mmol / g.

[0042] Weigh th...

Embodiment 3

[0050] Preparation of Fmoc-Gly-CTC Resin

[0051] The preparation of Fmoc-Gly-CTC Resin with a substitution value of 0.6mmol / g is as follows:

[0052] Weigh 100 g (120 mmol) of CTC resin with a substitution value of 1.2 mmol / g, add it to a solid-phase reactor, wash it twice with DCM, and after swelling the resin with DCM for 30 minutes, dissolve 71.3 g of Fmoc-Gly-OH in DCM, Put it into a solid-phase reactor, and then add 104.6ml of N,N-diisopropylethylamine (DIPEA) to react at room temperature for 3 hours. Then add 100ml of methanol for capping, and the capping time is 30 minutes. After end-capping, wash 3 times with DCM and 3 times with methanol. After drying, the Fmoc-Gly-CTC resin was obtained, and the detected substitution value was 0.6 mmol / g.

[0053] Preparation of semaglutide resin

[0054] Weigh the prepared Fmoc-Gly-CTC 66.7g (40mmol) with a substitution value of 0.6mmol / g, add it to the solid phase reactor, wash it twice with DMF, swell the resin with DMF for 3...

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PUM

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Abstract

The invention discloses a preparation method of semaglutide. The preparation method comprises: first preparing a semaglutide resin by a solid-phase peptide synthesis method, and then acidifying the semaglutide resin, and simultaneously removing the resin and a side chain protecting group to obtain crude semaglutide, and then purifying the crude semaglutide to obtain a refined semaglutide. The preparation method greatly reduces difficulties in the synthesis of semaglutide, effectively controls a ratio of racemic impurities, improves purity of the crude semaglutide, reduces amount of the used raw materials, and greatly reduces difficulties in purification, and has wide practical value and application prospect.

Description

technical field [0001] The present invention belongs to the field of preparation of polypeptide drugs, in particular to a preparation method of semaglutide. Background technique [0002] Semaglutide is a hypoglycemic drug developed by Novo Nordisk. This product can significantly reduce the level of glycosylated hemoglobin (HbA1c) and reduce weight in patients with type 2 diabetes, while greatly reducing the risk of hypoglycemia. Semeglutide is obtained by modifying and transforming GLP-1(7-37). Compared with Liraglutide, Semeglutide has a longer fatty chain and increased hydrophobicity, but Semeglutide has been modified with short-chain PEG to greatly enhance hydrophilicity. After PEG modification, it can not only bind tightly with albumin, cover the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, prolong the biological half-life and achieve the effect of long circulation. [0003] The CAS number of semaglutide: 910463-68-2, the English name semaglutide, ...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 吕爱平王升武
Owner 杭州肽佳生物科技有限公司
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