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Synthesis method of semaglutide

A synthetic method, the technology of semaglutide, applied in the field of peptide synthesis, can solve the problems of increasing the cost of raw materials and complicating the process, and achieve the effects of cost reduction, increased reaction yield, and simple process

Pending Publication Date: 2021-12-07
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the steric hindrance is reduced, it is divided into 6 fragments, which naturally increases the cost of raw materials and complicates the process at the same time

Method used

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  • Synthesis method of semaglutide
  • Synthesis method of semaglutide
  • Synthesis method of semaglutide

Examples

Experimental program
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preparation example Construction

[0068] The synthetic method of semaglutide of the present invention comprises the following steps:

[0069] a) Synthetic Fragment I:

[0070] Boc-His(Trt)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)- Tyr(Boc)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-Ala-OH;

[0071] b) Liquid phase synthesis of side chain monomer Fmoc-Lys(AEEA-AEEA-γ-Glu-OctadecanedioicAcid)-OH, the specific structure is as follows:

[0072]

[0073] c) Synthesis of Fragment II:

[0074] NH 2 -Lys(AEEA-AEEA-γ-Glu-Octadecanedioic Acid)-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Arg(pbf)-Gly-Arg(pbf)-Gly-OH.

[0075] d) Fragment I and fragment II are condensed and deprotected in liquid phase to finally obtain crude semaglutide peptide; the crude peptide is purified by high performance liquid phase to obtain semaglutide.

[0076] In the step a), the carrier resin is 2-CTC Resin resin, and the substitution degree of Fmoc-Ala-2CTC is 0.2-0.6mmol / g, preferably 0.3-0.5mmol / g;

[0077] ...

Embodiment 1

[0097] Embodiment 1 Fragment I synthesis

[0098] Select 10 g of Fmoc-Ala-CTC Resin amino acid resin with a substitution degree of 0.3 mmol / g, add it to the reaction column, add DMF to wash once, swell the DCM for 30 minutes, drain it, and add 20% piperidine / DMF solution to remove Fmoc , twice (5 minutes + 7 minutes), after removal, DMF washed 5 times, weighed Fmoc-Ala-OH (1.868g, 6mmol), HOBt (0.973g, 7.2mmol), added to the reaction column, DMF dissolved , then add DIC (1.22mL, 7.8mmol), react at room temperature for 1 hour, the ninhydrin detection reaction is complete, filter with suction, wash with appropriate amount of DMF 5 times, continue to repeat the above operation, and carry out Fmoc-Gln(Trt)-OH (3.664g , 6mmol), Fmoc-Gly-OH (1.784g, 6mmol), Fmoc-Glu(OtBu)-OH (2.553g, 6mmol), Fmoc-Leu-OH (2.120g, 6mmol), Fmoc-Tyr(Boc)- OH (2.757g, 6mmol), Fmoc-Ser(tBu)-OH (2.301g, 6mmol), Fmoc-Ser(tBu)-OH (2.301g, 6mmol), Fmoc-Val-OH (2.036g, 6mmol), Fmoc-Asp(OtBu)-OH (2.469g, 6mmo...

Embodiment 2

[0101] Embodiment 2 Fragment I synthesis

[0102] Select 10 g of Fmoc-Ala-CTC Resin amino acid resin with a substitution degree of 0.3 mmol / g, add it to the reaction column, add DMF to wash once, swell the DCM for 30 minutes, drain it, and add 20% piperidine / DMF solution to remove Fmoc , twice (5 minutes + 7 minutes), after removal, DMF washed 5 times, weighed Fmoc-Ala-OH (1.868g, 6mmol), HOBt (0.973g, 7.2mmol), added to the reaction column, DMF dissolved , then added DIC (1.22mL, 7.8mmol), reacted at room temperature for 2 hours, the reaction was detected by ninhydrin, filtered with suction, washed with appropriate amount of DMF for 5 times, continued to repeat the above operation, and carried out Fmoc-Gln(Trt)-OH (3.664g , 6mmol), Fmoc-Gly-OH (1.784g, 6mmol), Fmoc-Glu(OtBu)-OH (2.553g, 6mmol), Fmoc-Leu-OH (2.120g, 6mmol), Fmoc-Tyr(Boc)- OH (2.757g, 6mmol), Fmoc-Ser(tBu)-OH (2.301g, 6mmol), Fmoc-Ser(tBu)-OH (2.301g, 6mmol), Fmoc-Val-OH (2.036g, 6mmol), Fmoc-Asp(OtBu)-OH (2....

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Abstract

The invention relates to the technical field of polypeptide synthesis, and particularly relates to a synthesis method of semaglutide. The synthesis method comprises the following steps of: firstly, carrying out solid-phase synthesis on a fragment I (1-19 sites), and carrying out liquid-phase synthesis on a side chain monomer (20 site amino acid and a side chain thereof); then carrying out solid-phase synthesis on a fragment II (21-31 sites) coupled with the side chain monomer and other amino acids; and finally, condensing the fragment I and the fragment II, and refining to obtain the semaglutide. According to the synthesis method disclosed by the invention, a special synthesis strategy is adopted, the purity of crude peptide is increased, and the yield is greatly increased; meanwhile, the production period is shortened, the cost is reduced, and a fragment and side chain synthesis process is more beneficial for large-scale production; and meanwhile, the problem of palladium residues in three-waste treatment is solved.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a method for synthesizing semaglutide. Background technique [0002] Semaglutide is a long-acting GLP-1 analog developed by Nove Nordisk. On December 5, 2017, it was approved by the FDA and launched in the United States. [0003] Its structure (peptide sequence): [0004] H-His 7 -Aib 8 -Glu 9 -Gly 10 -Thr 11 -Phe 12 -Thr 13 -Ser 14 -Asp 15 -Val 16 -Ser 17 -Ser 18 -Tyr 19 -Leu 20 -Glu 21 -Gly 22 -Gln 23 -Ala 24 -Ala 25 -Lys 26 (AEEA-AEEA-γ-Glu-Octadecanedioic Acid)-Glu 27 -Phe 28 -Ile 29 -Ala 30 -Trp 31 -Leu 32 -Val 33 -Arg 34 -Gly 35 -Arg 36 -Gly 37 -OH [0005] AEEA is a special amino acid: 2-(2-(2-aminoethoxy)ethoxy)acetic acid. [0006] The specific structure is as follows: [0007] [0008] The existing synthetic technology of semaglutide can be roughly divided into two categories: [0009] The first type is gene recombina...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/08C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 袁慧星黄嘉诚汪伟尹传龙
Owner HYBIO PHARMA