A kind of method for preparing liraglutide

A technology of liraglutide and synthesis method, which is applied in the field of preparation of polypeptide drugs, and can solve problems such as long synthesis cycle, many impurities, and unsuitability for industrial production

Active Publication Date: 2016-08-31
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problems to be solved in the present invention are: long synthesis period, high cost, low yield, many impurities, unsuitable for industrialized production

Method used

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  • A kind of method for preparing liraglutide
  • A kind of method for preparing liraglutide
  • A kind of method for preparing liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment one: the synthesis of Palmitoyl-OSu activated lipid

[0090] Weigh 256.42g n-hexadecanoic acid (1.0mol), add 138.10g HOSu (1.2mol) into 2000ml THF, add 247.56g DCC (1.2mol) under ice-water bath, react for 1 hour, warm up to room temperature for 3 hours, and react Liquid filtration, mother liquor spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, 0-5°C ice ethanol Recrystallize 3 times, filter, and dry the solid oil pump to obtain 314.62g Palmitoyl-OSu activated lipid, yield 89%.

Embodiment 2

[0091] Embodiment two: the synthesis of Palmitoyl-Glu-OtBu

[0092] Weigh 101.62g H-Glu-OtBu (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to the mixed solution of 500ml water and 500ml THF to dissolve, and 176.75g Palmitoyl-OSu (0.5mol) was weighed and added to 500ml THF. Adjust the pH to 7 with dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The resulting white precipitate was recrystallized from 0-5°C ice-cold ethanol. The solid oil pump was dried to obtain 192.11g Palmitoyl-Glu-OtBu, yield 87%.

Embodiment 3

[0093] Example 3: Synthesis of Palmitoyl-Glu(OSu)-OtBu

[0094] Weigh 88.33g Palmitoyl-Glu-OtBu (0.2mol), add 27.62g HOSu (0.24mol) into 1000ml THF, add 49.51g DCC (0.24mol) under ice-water bath, react for 1 hour, warm up to room temperature for 3 hours, react Liquid filtration, mother liquor spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, 0-5°C ice ethanol Recrystallize 3 times, filter, and dry the solid oil pump to obtain 94.81g Palmitoyl-Glu(OSu)-OtBu activated fat, with a yield of 88%.

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Abstract

The invention relates to a technology for synthesizing liraglutide, which solves the problems of long synthesis period, high cost, low yield and many impurities in the prior art. The specific steps of the present invention are: A) synthesis of fragment Fmoc-Lys-(Glu(Nα-Palmitoyl)-OtBu)-OH through liquid phase; ‑OH coupling to obtain Fmoc‑Gly‑resin; C) By solid phase synthesis, amino acids with N-terminal Fmoc protection and side chain protection are sequentially coupled according to the peptide sequence of liraglutide main chain, in which the lysine tripeptide fragment Using Fmoc‑Lys‑(Glu(Nα‑Palmitoyl)‑OtBu)‑OH; D) to cleavage, purify, and lyophilize to obtain liraglutide. The invention provides a synthesis process of liraglutide with short synthesis period, low cost, high yield and suitable for large-scale production.

Description

technical field [0001] The present invention relates to a preparation method of polypeptide drugs, which is a synthetic long-acting type II diabetes drug-liraglutide with glucagon-like peptide-1 (GLP-1) receptor agonist method of preparation. Background technique [0002] Liraglutide, British name: Liraglutide, structural formula is as follows: [0003] [0004] The peptide sequence is: [0005] H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N-ε-(N-α -Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH [0006] Liraglutide is the first and currently only long-acting GLP-1 analog developed by Novo Nordisk, Denmark. Immunogenicity and other aspects are similar to GLP-1. The molecular structure of liraglutide is 97% homologous to GLP-1(7-37), and the structural difference is expressed in Lys 34 Replaced by Arg, Lys 26 Through glutamic acid-mediated palmitoylation, the fatty acid side chain can reversibly bind li...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K1/04C07K1/1077C07K14/605
Inventor 路杨杨东晖方晨周亮刘少华
Owner ADLAI NORTYE BIOPHARMA CO LTD
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