Synthesis method of liraglutide

A technology of liraglutide and synthetic methods, which is applied in the field of polypeptide drug synthesis, can solve the problems of unfavorable industrial production, cumbersome operation steps, low purity and yield, etc., to solve the difficult problem of coupling, reduce costs, and increase yield Effect

Pending Publication Date: 2019-03-12
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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Problems solved by technology

[0008] The technical problem to be solved by the present invention is to provide a new synthetic method of liraglutide for the problems of low purity and yield, high cost, cumbersome operation steps and unfavorable industrial production in the existing synthetic process. The method makes the synthesis of difficult sequences simple and easy to operate, and at the same time greatly improves the yield and purity of crude peptides, greatly reducing production costs

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  • Synthesis method of liraglutide
  • Synthesis method of liraglutide
  • Synthesis method of liraglutide

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Embodiment Construction

[0045] The technical solution of the method of the present invention is further described below, so that those skilled in the art can further understand the present invention, without constituting a limitation on the claims of the present invention.

[0046] One, the preparation of Fmoc-Gly-Wang resin

[0047] Weigh 100.0 g of Wang resin (Sub=0.61 mmol / g) and add it to a solid-phase reactor, add 350 mL of DCM to swell the resin for 0.5 h, and drain the solvent. Add 45.1g of Fmoc-Gly-OH and 30.5g of HOBt to 370ml of DMF solution and stir to dissolve. After cooling down to 5-8 degrees, add 30.5mL of DIC solution and stir. Add the activated solution to the resin and stir for 5h. Drain the solvent, add 11 mL of acetic anhydride, 8 mL of pyridine, and 160 mL of DMF, and block for 2 hours. DCM and methanol were alternately washed 3 times, 170 mL each time. After vacuum drying, the substitution degree of Fmoc-Gly-Wang resin is about Sub=0.55mmol / g.

[0048] 2. Fmoc-Val 10 -Ser 1...

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Abstract

The invention relates to a synthesis method of liraglutide, belonging to the field of polypeptide synthesis. The method synthesizes amino acids at 1st-31st positions of a main sequence of the liraglutide by means of a solid phase, and the 10th Val and the 11th Ser adopt Fmoc-Val10-Ser11(Psi(Me, Me)pro)-OH; the 20th Lys side chain adopts Fmoc-Lys(X)-OH, and the X is selected from Alloc, Dde, ivdde,Mtt, Pal-gamma-Glu-OtBu; the crude peptide of the liraglutide is obtained by means of cleavage precipitation; the liraglutide is obtained by means of purification. The method provided by the invention solves the problem of difficult sequence synthesis of the liraglutide by introducing Fmoc-Val10-Ser11(Psi(Me, Me)pro)-OH, thus enabling the synthesis of difficult sequences to be simple and easy tooperate; furthermore, the method greatly improves the yield and the purity of the ratio and the crude peptide, greatly reduces the production cost and facilitates industrial scale-up production.

Description

technical field [0001] The invention relates to the field of polypeptide drug synthesis, in particular to a synthesis method of liraglutide, a GLP-1 receptor kinetin. Background technique [0002] Chinese name: Liraglutide; English name: Liraglutide; peptide sequence: [0003] H-His 1 -Ala 2 -Glu 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Val 10 -Ser 11 -Ser 12 -Tyr 13 -Leu 14 -Glu 15 -Gly 16 -Gln 17 -Ala 18 -Ala 19 -Lys 20 (Pal-γ-Glu)-Glu 21 -Phe 22 -Ile 23 -Ala 24 -Trp 25 -Leu 26 -Val 27 -Arg 28 -Gly 29 -Arg 30 -Gly 31 -OH [0004] Liraglutide is the first long-acting GLP-1 analogue developed by Novo Nordisk, Denmark. It is 97% homologous to human glucagon-like peptide-1 (GLP-1). Liraglutide has various effects such as lowering blood sugar, promoting regeneration of islet cells, and slightly prolonging gastric emptying, and has broad application prospects. [0005] Chinese published patent document CN 103304660 discloses a synthesis metho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/16C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 赵呈青谷海涛施国强孙美禄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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