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Synthetic method of liraglutide

A synthesis method and technology of liraglutide, applied in the field of synthesis of liraglutide, can solve the problems of incomplete reaction, unfavorable separation and purification, high cost, improve purity and yield, facilitate purification operation, and reduce impurities the effect of

Active Publication Date: 2014-09-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When using gene recombination technology to synthesize liraglutide, the technical difficulty is relatively high, and the cost is relatively high. 34 -The side chain of GLP-1(7-37)-OH is in unprotected state, with N α -hexadecanoyl-Glu(ONSu)-OtBu will produce more impurities during the reaction, which is not conducive to separation and purification; With many hydrophobic amino acids, the resin shrinks severely during the step-by-step coupling and the reaction is incomplete, resulting in a low yield. At the same time, there are many impurities in the crude peptide that are similar in nature to the product, making purification difficult

Method used

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  • Synthetic method of liraglutide
  • Synthetic method of liraglutide
  • Synthetic method of liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of the first polypeptide fragment

[0041] Weigh 40g of 2-CTC resin with a substitution degree of 0.5mmol / g and add it to the solid phase reaction column, wash with DMF twice, swell with DMF for 30min, wash with DMF twice, add Fmoc-Thr(tBu)-OH (31.80g, 80mmol) and DIPEA (14ml, 80mmol) were dissolved in DMF, ice-bathed for 10min, and then added to the above solid-phase reaction column, stirred and reacted with nitrogen for 5 minutes, then added 14ml DIPEA again, continued to react for 1h, and added 12.8g MeOH to seal for 20 minutes, The reaction solution was drained and washed 6 times with DMF to obtain Fmoc-Thr(tBu)-2-CTC resin.

[0042] Add 20% DBLK to Fmoc-Thr(OtBu)-2-CTC resin for deprotection (6+6min), wash with DMF 6 times, Fmoc-Phe-OH (30.99g, 80mmol), HOBt (11.35g, 84mmol) Dissolve PyBOP (41.63g, 80mmol) in DMF, ice bath for 10 minutes, add 27.9ml DIPEA to activate for 5 minutes, then add to the above solid-phase reaction column, stir and r...

Embodiment 2

[0046] Example 2 Preparation of the second polypeptide fragment

[0047] Weigh 40g of 2-CTC resin with a substitution degree of 0.5mmol / g and add it to the solid phase reaction column, wash it twice with DMF, swell with DMF for 30min, wash twice with DMF, add Fmoc-Glu(OtBu)-OH (35.04g, 80mmol) and DIPEA (14ml, 80mmol) were dissolved in DMF, ice-bathed for 10min, and then added to the above solid-phase reaction column, stirred and reacted with nitrogen for 5 minutes, then added 14ml DIPEA again, continued to react for 1h, and added 12.8g MeOH to seal for 20 minutes, The reaction solution was drained and washed 6 times with DMF to obtain Fmoc-Glu(OtBu)-2-CTC resin.

[0048] Add 20% DBLK to Fmoc-Glu(OtBu)-2-CTC resin for deprotection (6+6min), wash with DMF 6 times, Fmoc-Leu-OH (28.28g, 80mmol), HOBt (11.35g, 84mmol) Dissolve PyBOP (41.63g, 80mmol) in DMF, ice bath for 10 minutes, add 27.9ml DIPEA to activate for 5 minutes, then add to the above solid-phase reaction column, stir...

Embodiment 3

[0052] Example 3 Preparation of the third polypeptide fragment

[0053] Weigh 40g of 2-CTC resin with a substitution degree of 0.5mmol / g and add it to the solid phase reaction column, wash it twice with DMF, swell with DMF for 30min, wash twice with DMF, add Fmoc-Glu(OtBu)-OH (35.04g, 80mmol) and DIPEA (14ml, 80mmol) were dissolved in DMF, ice-bathed for 10min, and then added to the above solid-phase reaction column, stirred and reacted with nitrogen for 5 minutes, then added 14ml DIPEA again, continued to react for 1h, and added 12.8g MeOH to seal for 20 minutes, The reaction solution was drained and washed 6 times with DMF to obtain Fmoc-Glu(OtBu)-2-CTC resin.

[0054] Add 20% DBLK to Fmoc-Glu(OtBu)-2-CTC resin for deprotection (6+6min), wash with DMF 6 times, Fmoc-Lys(Alloc)-OH (28.28g, 80mmol), HOBt (11.35g , 84mmol) and PyBOP (41.63g, 80mmol) were dissolved in DMF, ice-bathed for 10 minutes, added 27.9ml DIPEA to activate for 5 minutes, then added to the above solid-phas...

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Abstract

The invention relates to the field of polypeptide synthesis, and especially relates to a synthetic method of liraglutide. The method is as follows: peptide resin is obtained by successively coupling a third polypeptide fragment, a second polypeptide fragment and a first polypeptide fragment with a fourth polypeptide fragment-resin, and then the liraglutide is obtained by side chain modification, cracking, purification and freeze drying. By use of the synthetic method of the liraglutide, the purity and yield of crude peptide can be improved, and the method is conducive to the purification, can improve the yield of the product, shortens the synthesis time, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a synthesis method of liraglutide. Background technique [0002] With the improvement of living standards and changes in lifestyle, the incidence of diabetes in my country has been increasing year by year in recent years. Diabetes is caused by genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, mental factors and other pathogenic factors acting on the body, resulting in hypofunction of pancreatic islets, insulin resistance, etc., and then causing sugar, protein, fat, A series of metabolic disorder syndromes such as water and electrolytes, clinically characterized by hyperglycemia, typical cases may appear polyuria, polydipsia, polyphagia, weight loss and other symptoms, that is, "three more and one less" symptoms, once the control is not good It will cause complications, leading to failure and lesions in the kidneys, eyes, feet and o...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605
Inventor 陈友金潘俊锋覃亮政马亚平袁建成
Owner HYBIO PHARMA
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