Solid-phase synthesis method of Sermaglutide

A technology for semaglutide and solid-phase synthesis, which is applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve the problems of unfavorable large-scale production of semaglutide, high production cost, long synthesis cycle and the like, Achieve considerable economical value, improve condensation efficiency, and improve the effect of yield

Active Publication Date: 2017-03-08
合肥国肽生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Most of the existing semaglutide synthesis methods are solid-liquid synthesis methods. The synthesis method of CN201410573312.1 has a long synthesis cycle and high production cost, which is not conducive to the large-scale production of semaglutide

Method used

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  • Solid-phase synthesis method of Sermaglutide
  • Solid-phase synthesis method of Sermaglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 The transformation of lysine raw material

[0025] (1) Connection of side chain amino acids

[0026] Add 1 / 3-1 / 2 reactor volume of 20% piperidine / DMF deprotection solution to the drained reactor, place on a 30r / min decolorizing shaker and shake for 20min to remove the Fmoc side of lysine Chain protection group, according to the solid-phase amino acid condensation method, sequentially couple 2-(2-(2-aminoethoxy)ethoxy)acetic acid, 2-(2-(2-aminoethyl) on the side chain of lysine Oxy)ethoxy)acetic acid, Glu and octadecanedioic acid, after successful condensation, wash with DMF 5 times, and drain.

[0027] (2) Remove Dde protecting group

[0028] According to the configuration of hydrazine hydrate: DMF = 1:15 to remove the solution, eluted with a mixed solution of three times the volume of the resin each time, and washed 3 times with DMF after shaking for 5 minutes. After the third time, the hydrazine hydrate solution was removed. Second, the modified lysine...

Embodiment 2

[0029] Example 2 Synthesis of Semaglutide-2-Cl-Resin

[0030] 1.2 Swelling of Cl-Resin

[0031] Weigh 1g of 2-Cl-Resin with a substitution degree of 0.64mmol / g, add it to the polypeptide synthesis reactor from the open end, take the DCM reagent and add it to the reactor, so that the resin is completely immersed in the DCM solvent and fully contacted with the solvent , swelling for 0.5h.

[0032] 2. Synthesis of Semaglutide-2-Cl-Resin

[0033] Semaglutide-2-Cl-Resin is:

[0034] H-Aib-EGTFTSDVSSYLEGQAAK (Octadecanedioic-Glu-PEG2-PEG2) EFIAWLVRG RG-2-Cl-Resin

[0035] The protected amino acids used in this example are calculated from the resin, and the protected amino acids and molecular weights corresponding to the 1-31st amino acid are shown in the following table:

[0036]

[0037] Some commonly used abbreviations in the present invention have the following meanings:

[0038] Fmoc: fluorenylmethoxycarbonyl

[0039] DMF: N,N-Dimethylformamide

[0040] DCM: dichlorome...

Embodiment 3

[0060] Example 3 The cleavage and sedimentation of crude peptide products of semaglutide

[0061] (1) Configure cutting reagents

[0062] The 100ml formula is: 87.5mlTFA+5ml thioanisole+5ml water+2.5mlEDT+5g phenol, placed in a brown reagent bottle. It is now equipped for use, and the preparation amount is generally 1g resin plus 10ml cutting reagent.

[0063] (2) Cutting of semaglutide-2-Cl-Resin

[0064] Add the cleavage reagent to the drained reactor, place it on a decolorizing shaker and shake it for 1 hour at a speed of 20 r / min. After cutting, add about 35ml of glacial ether to a 50ml centrifuge tube, filter the solution in the reactor into glacial ether through a sand core, cover the cap of the centrifuge tube, shake the centrifuge tube up and down, and mix well. Put the centrifuge tube into the centrifuge, 3000r / min, 3min, centrifuge to discard the supernatant, repeat the operation 3 times to obtain the crude peptide product of semaglutide.

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Abstract

The invention discloses a solid-phase synthesis method of Sermaglutide. The method comprises steps of taking 2-Cl-Resin as an initial resin carrier; through a solid-phase synthesis method, orderly connecting the corresponding amino acids in a Sermaglutide sequence, wherein the lysine takes Dde-Lys (Fmoc)-OH as raw material; after linking the side chain raw material, removing Dde protection base of lysine, and performing continuous condensation reaction of a peptide chain; applying specific microwave technology treatment in a reaction process, and obtaining Sermaglutide-2-Cl-Resin; after cutting and settling Sermaglutide-2-Cl-Resin, freezing and drying, and obtaining crude peptide of Sermaglutide peptide. The method applies Fmoc solid-phase synthesis method, 2-Cl-Resin as solid phase carrier, and DIC/HOBt as the condensating agent, thus the lysine raw material is improved, the technical flow is largely simplified; the specific microwave synthetic technique is applied to the condensation reaction, thus the condensation efficiency is improved; the invention largely shortens the reaction time, improves the product yield, and has considerable economic application value and wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug synthesis, in particular to a solid phase synthesis method of semaglutide. Background technique [0002] Chinese name: semaglutide [0003] English name: Sermaglutide [0004] Sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(Octadecanedioic-Glu-PEG2-PEG2) -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH [0005] Molecular formula: C 187 h 291 N 45 o 59 [0006] Molecular weight: 4113.64 [0007] Sermaglutide, a novel long-acting glucagon-like peptide-1 (GLP-1) analog, administered once weekly subcutaneously, resulted in substantial improvements in blood glucose levels in patients with type 2 diabetes and the risk of hypoglycemia lower. At the same time, semaglutide can also induce weight loss by reducing appetite and reducing food intake. Compared with liraglutide, semaglutide has a longer fatty chain and strong hydrophobicity, but semagl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04
Inventor 陈为光孙良玉张旭光郑范娜陈御红
Owner 合肥国肽生物科技有限公司
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